Intermediates useful in the preparation of fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof

ABSTRACT

Chemical intermediates having the formula: ##STR1## wherein A represents an aromatic or heterocyclic ring system selected from benzene, a naphthalene, a quinoline or a pyridine in any of its four positions, any of the rings systems are optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro or trifluoromethyl; 
     R is selected from the group consisting of loweralkyl, cycloalkyl or phenylloweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl; 
     R 4  and R 5  are selected from hydrogen or loweralkyl; 
     n is 1 or 2; 
     X is selected from chlorine, bromine, or fluorine and E is selected from sulfur, oxygen or ##STR2## and chemical intermediates having the formula: ##STR3## wherein A, R, R 4 , R 5 , E and n are as defined above and Q is selected from the group consisting of ##STR4## wherein R 3  is hydrogen, an acid neutralizing ion or an esterifying radical; with the proviso that when n is 2 and E is oxygen, A is other than phenyl or substituted phenyl. 
     These chemical intermediates are useful in the preparation of oxazepinones, thiazepinones and diazepinones which exhibit antihistaminic activity.

REFERENCE TO PARENT APPLICATIONS

This application is a division of U.S. application Ser. No. 746,091,filed June 18, 1985, now U.S. Pat. No. 4,592,866, issued June 3, 1986,which is a continuation-in-part of U.S. application Ser. No. 652,058,filed Sept. 19, 1984, now abandoned, which is a continuation-in-part ofU.S. application Ser. No. 527,559, filed Aug. 29, 1983, now abandoned,which is a continuation-in-part of U.S. application Ser. No. 431,500,filed Sept. 30, 1982, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to novel aromatic oxazepinones,thiazepinones and diazepinones and sulfur analogs thereof and isparticularly concerned with aromatic 1,4-oxazepinones, thiazepinones,diazepinones and thiones of all, which have the aromatic component fusedinto the oxazepine, thiazepine or diazepine component, each componentthereby having two commonly shared carbon atoms and the oxazepine,thiazepine or diazepine ring having an oxo (or thioxo) function on thecarbon atom adjacent to one of the shared carbon atoms and a short chainaminoalkyl, alkylaminoalkyl or heterocyclicaminoalkyl radical attachedto the carbon atom two positions away from the other shared carbon atom,the compounds having antihistaminic and anti-allergy utility, and anovel process and novel intermediates for the preparation thereof.

2. Information Disclosure Statement

3-Aryl-1,4-benzoxazepin-5(4H)-ones substituted on the oxazepine nitrogenby an aminoalkyl radical have been disclosed by Schenker, K. in SwissPat. No. 505.850 (C.A. 75 98600s).

Conversion of flavanones into benzoxazepinones substituted in the2-position by a phenyl radical has been disclosed by Levai, A. andBognar, R., Top. Flavanoid Chem. Biochem. Proc. Hung. Bioflavonoid Symp.4th Ed. 1973 (Pub. 1975) 119-23 (C.A. 85, 79098n). Thione derivativeswere obtained by treating with phosphorus pentasulfide.

Certain chemical intermediates, the 1-substituted-3-substitutedphenoxypyrrolidines illustrated by

1-methyl-3-(2-carbamoylphenoxy)pyrrolidine,

1-benzyl-3-(2-carbamoylphenoxy)pyrrolidine, and

1-methyl-3-(2-carboxyphenoxy)pyrrolidine,

in an otherwise novel class are disclosed in U.S. Pat. No. 3,577,415.

OBJECTS AND SUMMARY OF THE INVENTION

The oxazepine, thiazepine and diazepine derivatives of the presentinvention which exhibit antihistaminic activity have the formula:##STR5## wherein;

A represents an aromatic ring having two of its carbon atoms heldmutually with the oxazepine, thiazepine or diazepine moiety selectedfrom the group consisting of benzene, naphthalene, a quinoline, or apyridine in any of its four positions, any of the rings optionallysubstituted by one or two Y radicals selected from the group consistingof halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, ortrifluoromethyl;

E is selected from oxygen, sulfur or loweralkyl substituted nitrogen,

B is selected from oxygen or sulfur;

R is selected from the group consisting of hydrogen,

loweralkyl, cycloalkyl or phenyl-loweralkyl, of which phenyl may beoptionally substituted by one or two radicals selected from halo,loweralkyl, loweralkoxy, nitro or trifluoromethyl;

n is 1, 2 or 3;

R⁴ and R⁵ are selected from hydrogen or loweralkyl (1-5 C);

Z is selected from the group consisting of --NR¹ R², 1H-pyrazol-1-yl,1H-imidazol-1-yl, 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl;

R¹ and R² are selected from the group consisting of hydrogen,loweralkyl, cycloalkyl and phenyl-loweralkyl, of which phenyl may beoptionally substituted by 1 or 2 radicals selected from halo,loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, or R¹ and R²taken together with the adjacent nitrogen atom may form a heterocyclicresidue selected from the group consisting of 1-azetidinyl,1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl,1-piperidinyl, 4-substituted piperidin-1-yl,4-[bis(4-fluorophenyl)methyl]-piperidin-1-yl, 4-morpholinyl,1-piperazinyl, 4-substituted piperazin-1-yl,1,2,3,6-tetrahydropyridin-1-yl, 1H-pyrrol-1-yl or2,5-dihydro-1H-pyrrol-1-yl; the optical isomers thereof; and thepharmaceutically acceptable salts thereof with the proviso that whenR═H, Z is never a primary or secondary amine, and a further proviso thatwhen n═3, Z is not pyrazolyl, or imidazolyl.

The novel oxazepine, thiazepine and diazepine precursors leading tocompounds of Formula I have the formula: ##STR6## wherein A, B, E, R,R⁴, R⁵ and Y are as defined under Formula I above, except R is nothydrogen, n is 1 or 2, and X is chlorine, bromine, cyano, or1-phthalimido;

the optical isomers thereof; and the acid addition salts thereof.

Other chemical intermediates in the preparation of compounds of FormulaII are novel and have the formula: ##STR7## wherein A, E, R, R⁴, R⁵, nand Y are as defined under Formula II above and X is chlorine orbromine.

Other chemical intermediates leading to compounds of Formula III havethe formula: ##STR8## wherein A, E, R, R⁴, R⁵, n and Y are as definedunder Formula II, and Q is selected from ##STR9## where R³ is H, alkalimetal ion or an esterifying radical. Compounds of Formula IVa are novelexcept wherein A is phenyl or substituted phenyl and E is oxygen when nis two.

Other chemical intermediates used in alternate procedures for preparingcompounds of Formula I and which are not precursors of Formula III typecompounds have the formulas V and VI. ##STR10## wherein A, R¹, R², R⁴and R⁵ have the values assigned under Formula I, and R³ is H or alkalimetal ion. Compounds of Formulas V and VI are not part of the presentinvention but are intended to be the subject of a separate application.

In the further definition of symbols in the formulas hereof and wherethey appear elsewhere throughout this specification and the claims, theterms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified,includes straight and branched chain radicals of up to eight carbonsinclusive and is exemplified by such groups as methyl, ethyl, propyl,isopropyl, butyl, sec.butyl, tert.butyl, amyl, isoamyl, hexyl, heptyland octyl radicals and the like. The term "loweralkoxy" has the formula--O--loweralkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing 3-9 carbon atoms inclusive and includes such groupsas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl,cycloheptyl and the like.

The terms "halo" or "halogen" when referred to herein include fluorine,chlorine, bromine and iodine unless otherwise stated.

"Pharmaceutically acceptable salts" include acid addition salts,hydrates, alcoholates and quaternary salts of the compounds of FormulaI, which are physiologically compatible in warm-blooded animals. Theacid addition salts may be formed by either strong or weak acids.Representative of strong acids are hydrochloric, sulfuric and phosphoricacids. Representative of weak acids are fumaric, maleic, succinic,oxalic, citric, tartaric, hexamic, and the like.

Suitable quaternary salts include the loweralkyl halides and loweralkylsulfates.

By "sulfurizing agent" is meant any agent or mixture of agents whichwill convert diazepinones, ox- and thiazepinones to diazepine-thiones,ox- and thiazepinethiones, such as2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson) reagent or a mixture of phosphorus pentasulfide andalkalimetal sulfide or mixture of phosphorus pentasulfide in a suitablesolvent such as acetonitrile, toluene or pyridine. By the use of"sulfurizing agent" the azepinones are thereby "sulfurized" toazepine-thiones.

The compounds of the present invention exhibit antihistaminic activityin guinea pigs. The method of testing is a modification of the procedureof Tozzi et al (Agents and Actions, Vol. 4/4, 264-270, 1974) as follows:Guinea pigs are fasted 18-24 hrs in individual cages. Water is availablead libitum. On the test day, animals in groups of 3 are injectedintraperitoneally with 30 mg/kg of the test compound prepared in anappropriate vehicle. Thirty minutes later histamine at a dosage level of1.2 mg/kg (=2×the LD₉₉) is injected into a marginal ear vein. Survivalof the guinea pigs for 24 hrs is positive evidence of antihistaminicactivity. If the vehicle used for the test compound is other than water,its effect is established by tesing an equal amount as a control. Thedose protecting 50% of the animals (PD₅₀) from death may be establishedfrom dose-response curves. The non-sedative nature of the compounds isdiscussed hereinbelow under "Additional Pharmacology."

The novel process of this invention comprises the following steps:

Step (1) Halogenating a compound of the formula ##STR11## wherein;

A represents an aromatic ring selected from benzene, naphthalene, aquinoline, or a pyridine in any one of its four positions, any of therings optionally substituted by one or two Y-radicals selected fromhalo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, ortrifluoromethyl;

E is oxygen, sulfur, or loweralkyl substituted nitrogen,

R is selected from the group consisting of loweralkyl, cycloalkyl orphenyl-loweralkyl, of which phenyl may be optionally substituted by oneor two radicals selected from halo, loweralkyl, loweralkoxy, nitro ortrifluoromethyl;

R³ is hydrogen or an acid neutralizing ion;

R⁴ and R⁵ are hydrogen or loweralkyl (1-5 C); and

n is one or two,

to give a compound of the formula ##STR12## or its free base wherein Xis chlorine or bromine and A, E, R, R⁴, R⁵, Y and n are the same as thestarting values. Among suitable halogenating agents are

(a) thionyl halides

(b) triphenylphosphine and a carbon tetrahalide

(c) phosphorus pentahalides

(d) phosphorus trihalides, and

(e) triphenylphosphine dihalide.

Step (2) Neutralizing, if necessary, and fusing the carboxylic acidhalide derivative prepared in step 1 to give an oxazepinone,thiazepinone or diazepinone of the formula ##STR13## wherein A, E, R,R⁴, R⁵, X, Y and n are as defined above in step 1, and A now has two ofits carbon atoms held mutually with the oxazepine, thiazepine, ordiazepine moiety;

Step (3) Optionally reacting the compound prepared in step 2 with asulfurizing agent to obtain an oxazepinethione, thiazepinethione, ordiazepinethione of the formula ##STR14## wherein A, E, R, R⁴, R⁵, X, Yand n are as defined above in step 2.

Step (4) When required, reacting a compound prepared in step 2 with analkali-metal cyanide to obtain a compound of the formula ##STR15##wherein A, E, Y, R, R⁴ and R⁵ are as defined in step 2,

Step (5) Reacting a halogen compound prepared in step 2 or 3 with acompound of the formula ZH

wherein Z is selected from --NR¹ R², 1H-pyrazol-1-yl, 1H-imidazol-1-yl,1H-imidazol-2-yl, or 4,5-dihydro-1H-imidazol-2-yl, and wherein R¹ and R²are selected from hydrogen, loweralkyl, cycloalkyl andphenyl-loweralkyl, of which phenyl may be optionally substituted with 1or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro,trifluoromethyl or cyano, or R¹ and R² taken together with the adjacentnitrogen atom may form a heterocyclic residue selected from the groupconsisting of 1-azetidinyl, 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl,2-methylpyrrolidin-1-yl, 1-piperidinyl, 4-substituted-piperidine-1-yl,4-[bis(4-fluorophenyl)methyl]piperidin-1-yl, 4-morpholinyl,1-piperazinyl, 4-substituted-piperazin-1-yl1,2,3,6-tetrahydropyridine-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,1H-pyrrol-1-yl, or 1-phthalimidyl to give the compound of the formula##STR16## wherein A, E, R, R⁴, R⁵, n and Y are as defined above in step2, Z is the same as in the ZH compound, and B is an oxygen or sulfuratom,

Step (6) Optionally reacting a compound prepared in step 5 wherein B isan oxygen atom with a sulfurizing agent, preferably phosphoruspentasulfide in pyridine to obtain a compound of the formula ##STR17##wherein A, E, R, R⁴, R⁵, n, Y and Z are as defined in step 5.

Step (7) Reducing a cyano compound (Formula IIc) prepared in step 4, orreacting a phthalimido compound prepared in step 4 with hydrazinehydrate to give a primary amine of the formula ##STR18## wherein A, E,Y, R, R⁴ and R⁵ are defined in steps 2 and 4.

Step (8) When required, reacting a primary amine prepared in steps 5 or7 of the formula ##STR19## wherein A, E, Y, R, R⁴ and R⁵ are as definedin step 2 with one of the following reactants or sets of reactants:

(a) formaldehyde and formic acid to give a tertiary dimethylamine,

(b) a dihalide or alkenedihalide to give a heterocyclic amine,

(c) a dialdehyde and sodium cyanoborohydride to give a heterocyclicamine,

(d) equal molar amounts of aldehyde or ketone, sodium cyanoborohydridewith large excess of above primary amine to give a secondary amine,

(e) equal molar amounts of the primary amine and sodium cyanoborohydridewith at least two equivalents of aldehyde or ketone,

(f) in sequence: trifluoroacetyl chloride, alkyl or phenyl-alkyl halide,potassium hydride and potassium hydroxide to give a secondary amine,

all products being encompassed by the formula ##STR20## wherein A, E, Y,R, R⁴ and R⁵ are as defined in step 2 and Z is --NR¹ R² wherein R¹ andR² are loweralkyl, cycloalkyl and phenyl-loweralkyl with phenyl beingoptionally substituted by halo, loweralkyl, loweralkoxy, nitro,trifluoromethyl or cyano or R¹ and R² taken together with the adjacentnitrogen may form a heterocyclic residue selected from 1-azetidinyl,1-pyrrolidinyl, 1-piperidinyl, 4-substituted-piperidin-1-yl,4-[bis(4-fluorophenyl)methyl]piperidin-1-yl, 4-morpholinyl,1-piperazinyl, 4-substituted-piperazin-1-yl,1,2,3,6-tetrahydropyridin-1-yl, 1H-pyrrol-1-yl or2-methylpyrrolidin-1-yl, and optionally sulfurizing the diazepinone,azepinone or thiazepinone to give the corresponding thione as in step 6.

Step (9) When required, reacting a benzyl or substituted benzyl compoundobtained in steps 5, 6, or 8 wherein Z is tertiary amino, ornon-reactive heterocycle radical such as pyrazolyl or imidazolyl of theformula ##STR21## wherein A, E, Y, R⁴ and R⁵ are as defined in step 2,and Z is a radical taken from the definition of Z under Formula Isubject to the same provisos given thereunder, with sodium and ammoniato give a compound of the formula ##STR22## wherein A, E, Y, R⁴ and R⁵are as defined in step 2, n is 1 to 3 and Z is the same as the startingcompound in this step,

Step (10) Optionally reacting the free base of any compound prepared insteps 5 to 9 with a pharmaceutically acceptable acid or quaternaryforming halide or sulfate to form a pharmaceutically acceptable saltthereof and, as explained hereinbelow, optically active compounds areobtained by using optically active starting compounds in step 1.

The compounds of Formula I wherein n is 2 are preferred for theirantihistaminic activity. The process which includes steps 1 to 3, 5, 6and 10 wherein compounds prepared have a methyl or ethyl side chain (n═1or 2) represents a preferred process corresponding to a succession ofsteps designated A to F as explained hereinbelow.

The compounds of Formulas I_(a), I_(b), I_(c-1) to I_(c-7), I_(c-1a)I_(d), I_(e), and I_(f) are all encompassed by Formula I and thecompounds of Formulas II_(a), II_(b), II_(c), II_(d) and II_(e) are allencompassed by Formula II.

Steps 1 to 4 also represent a novel process for preparing compounds ofFormula II_(a), II_(b), II_(c), all encompassed by Formula II.

It is therefore an object of the present invention to provide certainnovel aromatic 1,4-oxazepinones, thiazepinones and diazepinones andsulfur analogs thereof as described hereinabove under "Field ofInvention" and as defined by Formula I which have antihistaminicactivity.

Another object is to provide certain novel aromatic 1,4-oxazepinones,thiazepinones and diazepinones (and sulfur analogs thereof) substitutedwith haloalkyl or cyanoalkyl and phthalimidoalkyl radicals which arechemical intermediates as defined by Formula I.

Still another object is to provide a novel route and process forpreparation of aromatic 1,4-oxazepinones, thiazepinones, diazepinonesand sulfur analogs thereof substituted with short chain haloalkyl,cyanoalkyl or aminoalkyl radicals.

Additional objects and advantages of the present invention will beapparent to one skilled in the art and others will become apparent fromthe following description of the best mode of carrying out the presentinvention and from the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses the novel diazepine, oxazepine andthiazepine derivatives set forth in Formulas I and II and certain novelcompounds of Formulas III, IVa and IVb as composition of matter and aprocess for the preparation of compounds of Formulas I, II and III.

Charts I and II illustrate the preparation of all intermediates. R isnever hydrogen.

Chart III illustrates reaction sequence for preparing end-productswherein R is other than hydrogen and n is 1 or 2.

Chart IV illustrates preparation of compounds having ethyl and propylradicals-omega substituted by primary amine (--NH₂). R is neverhydrogen.

Chart V illustrates methods of converting the omega-NH₂ -substitutedethyl and propyl compounds to secondary and tertiary amines. This is analternate method for preparing the ethyl-secondary and tertiary amines.R is never hydrogen.

Chart VI illustrates preparation of compounds wherein R is hydrogen.

Preparations 1-40 and 42-51 illustrate syntheses of compounds ofFormulas IVa, IVb or provide certain starting materials therefor.

Preparation 41 provides a starting material for an alternate process.See Chart VIII, Formula VI. Intermediates 1-78 (see also Table 1)illustrate preparation of compounds encompassed by Formula II, which arechemical intermediates substituted with haloalkyl, cyanoalkyl, orphthalimidoalkyl radicals. The compounds of Formula II are formed in thereaction mixture usually without isolation.

Charts VII and VIII illustrate the preparation of compounds of Formula Iby novel alternate methods illustrated further in Examples 68b, 90 and107 to 109, which process methods thereof are not part of the presentinvention but which process methods are the subject of a separateapplication, U.S. Ser. No. 652,017 filed Sept. 19, 1984.

Examples 1-152 (see also Table 2) illustrate preparation of compoundsencompassed by Formula I. The scope of the invention is not limited bythe preparations, intermediates and examples, however. ##STR23##

Compounds of Formulas I and II have a chiral center in the oxazepine,thiazepine or diazepine moiety at the site of the carbon carrying theside-chain and therefore there is potential for separation of theenantiomers (optical isomers) or for synthesis of the enantiomers usingalready resolved starting chemicals or chemical intermediates. Such asynthesis for n=2 using resolved chemicals is outlined in Chart IX.Thus, by way of further amplification of possible methods of preparationof enantiomers of Formula I and II, one or more of the followingprocedures may be involved:

(a) resolving a racemic mixture of a compound of Formula I or II usingoptically active acids and separating the salts;

(b) preparing optically active compounds of Formula I from opticallyactive compounds of Formula II prepared in (a) preceding, (c) or (d)following;

(c) starting the synthesis with known optically active enantiomers, forexample, (S) or (R) malic acids illustrated in Chart IX. The method issuitable only when the E to carbon bond is not broken;

and (d) resolving one of the precursors of compounds of Formula II andproceding with the synthesis illustrated in Chart IX.

Preparation of enantiomers of compounds of Formula I and II weredemonstrated by combinations of procedures (b), (c), and (d), seePreparations 42-47, Intermediates 65-67 and Examples 125 and 126.

One of the intermediates, (S)-1-methyl-3-pyrrolidinol, was synthetizedwith retention of optical purity as shown in Chart IX starting with(S)-malic acid. The (S)-1-methyl-3-pyrrolidinol was shown to bedextrorotatory. As an alternative method of obtaining the resolvedisomers of 1-methyl-3-pyrrolidinol, the racemic mixture was treated with(2S,3S)-tartaric acid in methanol. The resulting crystals, after onerecrystallization, were converted to the base. This base was thedextrorotatory (S)-1-methyl-3-pyrrolidinol identical to that producedfrom (S)-malic acid.

The levorotatory (R)-1-methyl-3-pyrrolidinol was made in the same mannerusing (2R,3R)-tartaric acid.

The synthesis illustrated in Chart IX was carried out on both the R andS isomers using the resolved 1-methyl-3-pyrrolidinols as the startingmaterial.

The lack of racemization at each step was demonstrated with NMR spectraby use of the optically active shift reagent technique. In eachintermediate and the final product, it was demonstrated that bothoptical isomers could be seen in the racemic mixture; however, none ofthe opposing isomers were detected in any of the resolved compounds.

The enantiomer active agent (Example 126):

(R)-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thioneis primarily responsible for the activity of the racemic mixture (activeagent of the compound of Example 12), at low dosage being considerablymore potent than the corresponding (S) isomer (active agent of Example125). ##STR24##

In reference to the processes and the process steps of the inventionsummarized above as they apply to the preparation of compounds ofFormulas I, II and III, the following further description is applicable.

In step 1, starting compounds of Formula IV_(b) (See Chart I) bearing acarboxylic acid or an acid neutralizing ion such as an alkali-metal saltthereof on the A ring ortho to the ether linkage as a substantially pureentity or preferably derived in a reaction mixture resulting fromhydrolysis of precursors bearing in the same ortho position, carbamoyl,cyano or carboxylic acid ester functions without substantial isolationof the carboxylic acid (or salt) compound from the reaction mixture, aretreated with any suitable halogenating agent such as are describedabove, preferably thionyl chloride or triphenyl phosphine and carbontetrachloride. The halogenation is conducted in any suitable organicsolvent, preferably a refluxing organic solvent or a refluxinghalogenating agent such as the preferred thionyl chloride. Temperaturesfor the chlorination over a wide range may be employed, for example,from room temperature to 100° C. or above; however, temperatures of50°-80° C. are preferred, which temperatures encompass that of refluxingchloroform or thionyl chloride. When excess halogenating agent such asthionyl chloride has been used as carrier, it is advantageouslyevaporated. When solvent such as chloroform is used, it may, but notnecessarily, be evaporated away. In any event a solution comprising asolvent and compounds of Formula III or a residue comprised of FormulaIII compounds, all of which are confirmed by infra-red analysis isavailable for use in the next step.

In step 2, the halogenated compounds of Formula III, prepared in step 1,if not already in a solvent, are solubilized with organic solvent,preferably chloroform and usually neutralized or basified preferablywith a tertiary amine such as triethyl amine, and then heated at atemperature and for a time sufficient to effect a fusion of the carbonylwith the basic nitrogen and cleavage of the cyclic amine and formationof the chloro or bromoalkyloxazepinone, thiazepinone or diazepinonecompounds of Formula IIa. If the tendency to fuse is sufficiently great,thr neutralization of basification may be eliminated. The Formula IIacompounds may be isolated by conventional means, for example, bypartitioning between a suitable organic solvent or mixture of solventsand aqueous acid or base followed by drying and evaporating the organiclayer and recrystallizing the residue from a suitable solvent.

In step 3, the compounds of Formula IIa may optionally be converted tothe oxazepinethione, thiazepinethione or diazepinethione (IIb) byheating together with sulfurizing agent in a suitable organic solventsuch as toluene acetonitrile. The thione (IIb) may be isolated byconventional means, preferably by partitioning between an organicsolvent and dilute alkali metal base and crystallizing from a suitablesolvent such as ethanol.

In step 4, an oxazepinone, thiazepinone or diazepinone (IIa) is reactedwith potassium cyanide in a hot protic solvent using a phase transfercatalyst such as tetrabutyl ammonium bromide. The resulting cyanocompound is then extracted into a suitable solvent such as ethylacetate, and the solution dried and evaporated. The residue is thenrecrystallized from suitable solvent such as a mixture of ethyl acetateand isopropyl ether or ethyl acetate alone. As will be realized, thecompounds produced have cyanomethyl and cyano-ethyl side chains (n=1 or2) which lead to side chain lengthening to amino propyl n=3 or as analternate starting material for lengthening of a methyl chain to aminoethyl.

In step 5, the oxazepinone, thiazepinone (IIa) or diazepinone obtainedin step 2 or the oxazepinethione and thiazepinethione (IIb) ordiazepinethione obtained in step 3 are reacted with pyrazole, imidazoleor with an amine of the formula NHR¹ R² wherein R¹ and R² have the valuegiven under Formula I above to give compounds of Formulas Ia and Ib,respectively. The latter reaction is preferably conducted in excessamine as in the instance of volatile methylamines. The free bases ofproducts of Formula Ia and Ib are isolated by conventional means byremoving volatiles and partitioning between dilute aqueous alkali metalbase and a solvent such as chloroform or methylene chloride followed byevaporation. The free base may be converted to a pharmaceuticallyacceptable salt with an appropriate acid and in the case of a quaternarysalt with a loweralkyl halide or sulfate and recrystallized byconventional means. The free bases may be recovered from the acidaddition salts, usually in a purer form, by again partitioning the saltbetween aqueous base and a suitable solvent followed by evaporation. Aswill be realized and as shown in Chart I, the side chain of theintermediate produced is limited to aminomethyl and aminoethyl (n=2).

In step 6, when it is desirable, a compound prepared in step 5 wherein Bis oxygen is sulfurized, preferably by refluxing in dry pyridine withphosphorus pentasulfide for several hours. The resulting thione isisolated by cooling the solution and partitioning between a suitablesolvent such as chloroform and an aqueous base and evaporating theorganic phase and isolating by conventional means.

In step 7, a cyano compound (IIc) prepared in step 4 which is adiazepinone, an oxazepinone or a thiazepinone is reduced, preferablywith hydrogen using Raney nickel catalyst at about 60° C. The primaryaminoethyl or aminopropyl compound (n=2 or 3) produced is isolated byconventional means, preferably as an acid addition salt which may beconverted back to the free base by partitioning between a suitablesolvent and aqueous base and thereafter drying and evaporating theorganic layer.

In step 8 (see Chart V), a primary amine is converted to a secondary ortertiary amine by a choice of reactants. The method provides a route tosecondary and tertiary amino compounds of Formula I having n=3 notafforded by step 5 and, in addition, provides an alternate route tosecondary and tertiary amino compounds of Formula I wherein n=1 or 2.The preparation of dimethylamino derivatives by reaction of primaryamine with formaldehyde and formic acid is a conventional method forpreparing tertiary dimethyl amines as is reaction of a dihalide to givea heterocyclic amine such as 1-pyrrolidino, piperidino or 4-morpholino.The alternatives employing sodium cyanoborohydride follow the proceduresdescribed by R. F. Borch et al, J. Amer. Chem. Soc. 93, 2897 (1971). Theprocedure which employs conversion to a trifluoroacetamide is describedby J. E. Norlander et al, Tetrahedron Letters, 1978 (50) pp 4987-4990.

In step 9, a 4-benzyloxyazepinone, 4-benzyl-thiazepinone or4-benzyldiazepinone derivative (R=benzyl) under Formula I excludingprimary or secondary amines is converted to the correspondingN-unsubstituted (R=H) oxazepinone, thiazepinone or diazepinone byreaction with sodium and ammonia and may be isolated as illustrated inExample 68a.

Step 10 is optional depending on whether the compound of Formula I isalready in the form of a pharmaceutically acceptable salt or whether itis desirable to convert to another salt or whether the free base isdesired. To obtain the free base from any addition salt of Formula I,the salt is partitioned between a suitable organic solvent such aschloroform and a dilute aqueous base. The organic layer is dried andcondensed to give the free base which is then, if desired, reacted withan acid described above to give the desired salt.

As mentioned above, the preferred steps for reaching the preferredcompounds having an ethyl side chain in the 2-position include steps 1to 3, 5, 6 and 10 of the general process for preparing all the compoundsof Formula I. Inasmuch as the compounds having a methyl side chain canbe made by the same process, compounds wherein n=1 are included in thepreferred process. These steps of a preferred process are designated Ato F corresponding to the numbered steps of the general process with thelimitation that n=1 or 2 and R is other than hydrogen as follows:

    ______________________________________                                                      Corresponding General                                                         Step Number with                                                Preferred Process                                                                           Description Pertaining                                          Step Designation                                                                            to n = 1 or 2                                                   ______________________________________                                        A             1                                                               B             2                                                               C             3                                                               D             5                                                               E             6                                                               F             10                                                              ______________________________________                                    

Compounds of Formula I wherein E is O or S are preferred because oftheir potency as antihistamines based on test comparisons made.

PREPARATION 1 2-(1-Benzyl-3-pyrrolidinyloxy)benzamide

To a suspension of 4.3 g (0.11 mole) of sodium amide in 60 ml of drytoluene was added 19.3 g (0.11 mole) of 1-benzyl-3-pyrrolidinol at arate to maintain a temperature of 35° C. Stirring was continued at roomtemperature for 3 hours. To the mixture was added at rapid drop 19 g(0.1 mole) of o-toluenesulfonyl chloride with ice bath cooling tomaintain a temperature of 20°-30° C. Stirring was continued at roomtemperature for 2.5 hours and the mixture allowed to stand overnight.The toluene was washed twice with water, dried with sodium sulfate andconcentrated.

To a suspension of 5.4 g (0.1 mole) of sodium methoxide in 50 ml ofdimethylformamide in another vessel was added 13.6 g (0.1 mole) ofsalicylamide in 75 ml of dimethylformamide at a rate to maintain atemperature of 50° C. After stirring 15 minutes, the above preparedsulfonate in 25 ml of dimethylformamide was added dropwise and thesolution refluxed 5 hours. The material was partitioned between 500 mlof ethyl acetate and 500 ml of water. The ethyl acetate was extractedwith dilute hydrochloric acid, the acid basified with dilute sodiumhydroxide and extracted with ethyl acetate. The organic layer was dried,concentrated, and the residue crystallized twice from isopropylether-ethyl acetate. Yield of product was 12.5 g (42%), m.p. 120.5°-122°C.

Analysis: Calculated for C₁₈ H₂₀ N₂ O₂ : C, 72.95; H, 6.80; N, 9.46.Found: C, 73.23; H, 6.78; N, 9.56.

PREPARATION 2 2-(1-Methyl-3-pyrrolidinyloxy)benzamide

To 85.6 g (2.2 moles) of sodium amide in 1.5 liter of dry toluene wasadded 202 g (2 moles) of 1-methyl-3-pyrrolidinol so as not to exceed atemperature of 50° C. The mixture was then heated to 70° C. for 4.5hours. The mixture was cooled and 381 g (2 moles) ofo-toluenesulfonylchloride was added at a rapid drop while maintaining atemperature of 20°-30° C. with an ice bath. The mixture was stirred atroom temperature for 2.5 hours and washed with water. The toluenesolution was dried with sodium sulfate and concentrated. The residue,dissolved in 500 ml of dimethylformamide, was added to a reactionmixture prepared by adding 119 g (2.2 moles) of sodium methoxide and 274g (2.0 moles) of salicylamide to one liter of dimethylformamide and themixture was worked up as in preparation 1. Yield of product was 170 g(38%), m.p. 116°-118° C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ : C, 65.43; H, 7.32; N, 12.72.Found: C, 65.28; H, 7.28; N, 12.77.

PREPARATION 3 2-[3-(1-Benzyl)pyrrolidinyloxy]benzoic acid

To a solution of 20.3 g (0.52 mole) of sodium hydroxide in 600 ml ofethanol and 400 ml of water was added 150 g (0.51 mole) of2-[3-(1-benzyl)pyrrolidinyloxy]benzamide and the mixture was stirred atreflux for 48 hours. The mixture was concentrated on the rotaryevaporator to one-half volume and the residue was extracted with ethylacetate to remove unreacted amide. The water layer was filtered and thepH of the filtrate adjusted to 6.5 with hydrochloric acid. The filtratewas concentrated on the rotary evaporator. The residue was dissolved inisopropyl alcohol. The resulting mixture was filtered and the filtrateconcentrated. The residue 85.7 g was comprised substantially of thetitle compound.

PREPARATION 4 3-[(1-Methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxamide

To a cooled solution of 68 g (0.67 mole) of 1-methyl-3-pyrrolidinol and74 g (0.73 mole) triethylamine in 700 ml of dry benzene was addeddropwise 74 g (0.63 mole) of methanesulfonyl chloride. After stirring atroom temperature for 45 min, the mixture was filtered and the filtrateconcentrated under reduced pressure and dissolved in 100 ml ofdimethylformamide.

To a cooled suspension of 10.8 g (0.45 mole) of sodium hydride in 75 ofdimethylformamide in another vessel, 84 g (0.45 mole) of3-hydroxy-2-naphthalenecarboxamide dissolved in 400 ml ofdimethylformamide was added dropwise. The above prepared sulfonatesolution was added dropwise and the reaction mixture stirred and heatedat reflux for 16 hr. The cooled solution was diluted with 1000 ml ofwater and extracted twice with 500 ml portions of chloroform. Thechloroform was washed with water and extracted twice with 500 mlportions of 3N hydrochloric acid. The aqueous extracts were madealkaline with 50% sodium hydroxide and extracted thrice with 500 mlportions of chloroform. After drying over magnesium sulfate, thechloroform was evaporated under reduced pressure affording 27.4 g (22%)of a pale yellow solid. Recrystallized from ethyl acetate,m.p.=128°-130° C.

Analysis: Calculated for C₁₆ H₁₈ N₂ O₂ : C, 71.09; H, 6.71; N, 10.36.Found: C, 70.88; H, 6.68; N, 10.37.

PREPARATION 5 3-[(1-Methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxylicacid oxalate[2:1]

To a solution of 21.6 g (0.54 mole) of sodium hydroxide in 500 ml ofwater was added 74 g (0.27 mole) of3-[1-methyl-3-pyrrolinyl)oxy]-2-naphthalenecarboxamide. The solution washeated at reflux for 16 hrs and on cooling, the pH was adjusted to 6.8with concentrated hydrochloric acid. The resultant solid was separatedby filtration and the pH of the filtrate was adjusted to 6.02. Thefiltrate was concentrated under reduced pressure and the residue boiledin 200 ml of isopropyl alcohol and filtered. The filtrate was againconcentrated under reduced pressure to give 69 g (94%) of an amorphoussolid. An aliquot was dissolved in isopropanol and treated with oxalicacid. The oxalate salt was recrystallized from ethanol/water, m.p.209°-212° C.

Analysis: Calculated for C₁₇ H₁₈ NO₅ : C, 64.55; H, 5.74; N, 4.43.Found: C, 63.86; H, 5.68; N, 4.37.

PREPARATION 6 Sodium2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate

To a stirred suspension of 6.4 g (0.13 mole) of 50% sodium hydride(mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g(0.063 mole) of 1-methyl-3-pyrrolidinol. During addition, thetemperature rose from 25° C. to 31° C. After 10 minutes, a solution of10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml ofdimethylsulfoxide was added dropwise causing the temperature to rise.When the temperature reached 55° C., it was maintained there by theintermittent use of an ice bath until addition was complete. The mixturewas then heated to 55°-60° C. for 1.5 hr., cooled and filtered. Thefilter cake was suspended in 100 ml of ethyl acetate and filtered. Thesolid was recrystallized from ethyl acetatemethanol. Yield of productwas 5 g., dec. 240° C. The NMR analysis showed that the compoundcontained 1/3 mole of sodium acetate as impurity.

Analysis: Calculated for C₁₁ H₁₃ N₂ O₃ Na.1/3C₂ H₃ O₂ Na: C, 51.62; H,5.20; N, 10.32. Found: C, 51.81; H, 5.15; N, 10.39.

PREPARATION 7 4-Chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide

To a solution of 55.5 g (0.55 mole) of triethylamine in 500 ml of drybenzene was added dropwise 50.5 g (0.50 mole) of 1-methyl-3-pyrrolidinolat such a rate as to maintain a temperature of 25°-35° C. To themixture, maintained at 20°-50° C., was added dropwise, 57 g (0.50 mole)of methanesulfonyl chloride. After stirring for 1 hr at roomtemperature, the mixture was filtered and the precipitate washed with250 ml of hot benzene. The filtrate and wash were combined andconcentrated under reduced pressure and the residue dissolved in 200 mldimethylformamide.

To a cooled suspension of 19.6 g (0.41 mole) of sodium hydride in 100 mlof dimethylformamide in another vessel was added dropwise a solution of70 g (0.41 mole) of 4-chlorosalicylamide in 200 ml dimethylformamide ata rate such as to maintain a temperature of 20° C. To the resultingreaction mixture was added dropwise the above-prepared sulfonate saltand the mixture was heated at reflux for 19 hrs. The reaction mixturewas cooled and diluted with one liter of water. The diluted mixture wasextracted three times with 300 ml portions of chloroform. The chloroformextracts were combined and extracted with two 500 ml portions of 3Nhydrochloric acid. The combined aqueous extract was made alkaline with50% sodium hydroxide and extracted three times with 500 ml portions ofethyl acetate. The combined ethyl acetate extract was dried overmagnesium sulfate and concentrated under reduced pressure to give 46.5 g(45%) beige solid. The solid was recrystallized from ethyl acetate, m.p.122°- 123° C.

Analysis: Calculated for C₁₂ H₁₅ N₂ ClO₂ : C, 56.58; H, 5.94; N, 10.99.Found: C, 56.48; H, 5.96; N, 10.84.

PREPARATION 8 5-Bromo-2-[(-methyl-3-pyrrolidinyl)oxy]benzamide

To a cooled solution of 101 g (1.0 mole) 1-methyl-3-pyrrolidinol, 111 g(1.1 mole) triethylamine in 1000 ml of dry benzene was added dropwise114 g (1.0 mole) of methanesulfonyl chloride. The reaction mixture wasstirred at room temperature for 1 hour and filtered. The filtrate wasconcentrated under reduced pressure and dissolved in 100 mldimethylformamide.

To a cooled suspension of 30 g (0.63 mole) sodium hydride in 100 mldimethylformamide in another vessel was added dropwise5-bromosalicylamide (137 g, 0.63 mole) dissolved in 750 ml ofdimethylformamide. The above prepared sulfonate was added dropwise andthe reaction mixture heated at reflux for 18 hrs. The cooled solutionwas diluted with 1000 ml of water and extracted thrice with 500 mlportions of chloroform. The chloroform extracts were washed with waterand extracted four times with 500 ml portions of 3N hydrochloric acid.The aqueous layer was made alkaline with 50% sodium hydroxide andextracted with chloroform. The chloroform extracts were washed withwater, dried over magnesium sulfate and evaporated under reducedpressure to give 52 g (28%) of a yellow solid. The solid wasrecrystallized from ethyl acetate/chloroform, m.p. 160°-162° C.

Analysis: Calculated for C₁₂ H₁₅ N₂ BrO₂ : C, 48.18; H, 5.05; N, 9.36.Found: C, 48.02; H, 5.01; N, 9.22.

PREPARATION 9 5-Chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamidehemihydrate

To a cooled suspension of 2.4 g (0.41 mole) sodium hydride in 50 ml ofdimethylformamide was added dropwise 17 g (0.1 mole) of5-chlorosalicylamide dissolved in 50 ml of dimethylformamide at a ratesuch that the temperature did not exceed 20° C. After addition of thesalicylamide was complete, 16.7 g (0.1 mole) of3-bromo-1-methylpyrrolidine dissolved in 50 ml of dimethylformamide wasadded dropwise. The reaction mixture was stirred and heated at refluxfor 19 hr. The cooled solution was diluted with 250 ml of water andextracted twice with 250 ml portions of chloroform. The chloroform wasextracted thrice with 500 ml portions of 3N hydrochloric acid. Theaqueous extracts were made alkaline with 50% sodium hydroxide andextracted with ethyl acetate. Drying over magnesium sulfate andevaporation of the ethyl acetate under reduced pressure gave 6 g (23%)of product as a beige solid. The solid was recrystallized from ethylacetate, m.p. 126°-128° C.

Analysis: Calculated for C₂₄ H₃₂ N₄ Cl₂ O₅ : C, 54.65; H, 6.11; N,10.62. Found: C, 54.87; H, 6.12; N, 10.69.

PREPARATION 10 1-[(1-Methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxamide

A solution of 118 g (0.63 mole) of 1-hydroxy-2-naphthalenecarboxamide in250 ml of dimethylsulfoxide was added dropwise to a suspension of 27.6 g(0.69 mole) of 50% sodium hydride (mineral oil) in 250 ml ofdimethylsulfoxide. The reaction was exothermic and the temperature roseto 60° C.

In another vessel, 79 g (0.69 mole) of methanesulfonylchloride was addeddropwise to a solution of 69.7 g (0.69 mole) of 1-methyl-3-pyrrolidinoland 77 g (0.76 mole) of triethylamine in 500 ml of dry benzene whilecooling with an ice bath. The mixture was stirred 15 minutes andfiltered. The filter cake was washed with 500 ml of benzene and thebenzene filtrates were combined and concentrated on the rotaryevaporator to about 200 ml. The residue was added dropwise to the aboveprepared dimethylsulfoxide solution containing the sodium salt of1-hydroxy-2-naphthalenecarboxamide while stirring at 75° C. Thetemperature was maintained at 75° C. for 18 hr with external heat. Theresulting solution was cooled and an equal volume of water was added.The mixture was extracted with three portions of chloroform. The washeswere combined and concentrated. The residue was partitioned betweenethyl acetate and dilute hydrochloric acid. The acid layer was madebasic with sodium hydroxide and extracted twice with ethyl acetate. Theethyl acetate washes were combined, dried over sodium sulfate andconcentrated. The residue was crystallized from ethyl acetate-isooctane.Yield of solid was 55 g (32%). A portion was recrystallized twice fromethyl acetate-isooctane, m.p. 122°-129° C.

Analysis: Calculated for C₁₆ H₁₈ N₂ O₂ : C, 71.11; H, 6.71; N, 10.36.Found: C, 70.96; H, 6.71; N, 10.31.

PREPARATION 11 5-Methoxy-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide

To a solution of 151 g (1.5 mole) 1-methyl-3-pyrrolidinol and 166 g (1.6mole) triethylamine in 1500 ml of dry benzene was added dropwise 171 g(1.5 mole) of methanesulfonyl chloride with cooling. The reactionmixture was stirred at room temperature for one hour and filtered. Thefiltrate was concentrated under reduced pressure to give anorange-colored oil.

In another vessel, to a suspension of 50% sodium hydride/mineral oil (72g; 1.5 mole) in 150 ml of dimethylformamide the sulfonate prepared aboveand 139 g (0.93 mole) of 5-methoxy salicylamide dissolved in 600 mldimethylformamide were added dropwise with cooling. The reaction mixturewas heated at reflux for 14 hr. After cooling, the reaction was dilutedwith 1000 ml of water and extracted three times with 700 ml portions ofchloroform. The combined chloroform extracts were washed thrice withwater and extracted thrice with 500 ml portions of 3N hydrochloric acid.The aqueous layer was made alkaline and extracted with chloroform. Thechloroform extracts were washed thrice with water, dried over magnesiumsulfate and evaporated under reduced pressure to give a viscous brownoil. Vacuum distillation of this material yielded a viscous orange oilwhich was dissolved in chloroform, extracted in acid; made alkaline andextracted into chloroform again. Evaporation of the solvent gave a darkbrown oil which solidified under reduced pressure. Threerecrystallizations from ethyl acetate gave 10 g of white crystals (4%),m.p. 85°-87°.

Analysis: Calculated for C₁₃ H₁₈ N₂ O₃ : C, 62.38; H, 7.25; N, 11.19.Found: C, 62.47; H, 7.26; N, 11.20.

PREPARATION 12 3-[(1-Methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrilefumarate [1:2]

A solution of 55 g (0.55 mole) of 1-methyl-3-pyrrolidinol in 55 ml ofdry dimethylformamide was added dropwise to a suspension of 22 g (0.58mole) of 60% sodium hydride/40% mineral oil in 300 ml ofdimethylformamide. The mixture was stirred at room temperature for onehour and 73 g (0.53 mole) of 3-chloro-4-cyanopyridine in 200 ml ofdimethylformamide was added dropwise with mild cooling to maintain atemperature of 30°-40° C. The solution was stirred 3 hours and an equalvolume of water added. The solution was made acidic with dilutehydrochloric acid and extracted with isopropyl ether. The aqueous layerwas made basic with sodium hydroxide and extracted 5 times withchloroform. The extracts were combined, dried over sodium sulfate andconcentrated. The residue was treated with 50 g of fumaric acid in 400ml of isopropyl alcohol and 40 ml of water. The resulting crystals (51g; 21 %) were collected. A 2 g sample was recrystallized from methylisobutyl ketone. Yield of product was 1.5 g, m.p. 172°-174° C.

Analysis: Calculated for C₁₉ H₂₁ N₃ O₉ : C, 52.42; H, 4.86; N, 9.65.Found: C, 52.40; H, 4.90; N, 9.68.

PREPARATION 131-[(1-Methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarbonitrile oxalate

A solution of 29 g (0.11 mole) of1-[(1-methylpyrrolidinyl)oxy-2-naphthalenecarboxamide and 38 g (0.32mole) of thionyl chloride in 150 ml of chloroform was heated to refluxfor 6 hr. The solution was poured into ice and made basic with sodiumhydroxide. The chloroform layer was separated, dried over sodium sulfateand concentrated. The residue was dissolved in hot isooctane. Thesolution was treated with charcoal, filtered and concentrated. Theresidue was dissolved in isopropyl alcohol and oxalic acid was added.The precipitate was recrystallized from isopropyl alcohol-water mixture.Yield of product was 11.5 g (31%), m.p. 176°-184° C.

Analysis: Calculated for C₁₈ H₁₈ N₂ O₅ : C, 63.15; H, 5.30; N, 8.18.Found: C, 63.00; H, 5.29; N, 8.15.

PREPARATION 14 3,5-Diiodo-methylsalycilate

To one liter of absolute methanol was added 150 g (0.39 mole) of3,5-diiodosalicylic acid. Hydrogen chloride was bubbled through thereaction mixture under agitation and refluxed for 3 hrs. The reactionmixture turned cloudy and suddenly a large volume of white crystalsprecipitated. The mixture was filtered to give, after drying, 136 g(83%) of product, m.p. 198°-202° C.

PREPARATION 15 2-Hydroxy-3,5-diiodobenzamide

A stainless steel bomb, cooled with dry ice acetone, was charged withexcess liquid ammonia, 3,5-diiodomethylsalicylate and a catalytic amountof sodium hydride. The bomb was sealed and shaken at room temperaturefor 16 hrs. On cooling again, the contents of the bomb were poured outand excess ammonia allowed to evaporate at room temperature. The productmelted 190°-195° C. with decomposition. Mass spec analysis confirmedmolecular weight of the title compound.

PREPARATION 16 3,5-Diiodo-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide

Following the procedure of preparation 1, substituting2-hydroxy-3,5-diiodobenzamide for salicylamide, the title compound isprepared.

PREPARATION 17Sodium-2-[(1-methyl-3-azetidinyl)oxy]-3-pyridinecarboxylate

The title compound is prepared by following the procedure of preparation6 but substituting 1-methyl-3-azetidinol for 1-methyl-3-pyrrolidinol.

PREPARATION 18 4-[(1-Methyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylicacid sodium salt

4-Chloropyridine is reacted with diisopropyl lithium amide and carbondioxide to give the lithium salt of 3-carboxy-4-chloropyridine which isthen reacted with 1-methyl-3-pyrrolidinol as in Preparation 6.

PREPARATION 19 3-[(1-Methyl-3-pyrrolidinyl)oxy]-2-pyridinecarbonitrilefumarate

2-Carboxamido-3-hydroxypyridine is reacted with ##STR25## to give2-cyano-3-chloropyridine which is then reacted with1-methyl-3-pyrrolidinol as in preparation 12 to give the title compound.

PREPARATION 20 1-Methyl-3-pyrrolidinethiol acetate (ester) ethanedioate

To a solution of 101 g (1 mole) of 1-methyl-3-pyrrolidinol and 110 g(1.1 mole) of triethylamine in 700 ml of dry benzene was added dropwise115 g (1 mole) of methanesulfonyl chloride while stirring and coolingwith an ice bath. The resulting mixture was stirred for 0.5 hr. andfiltered. The filtrate was concentrated on the rotary evaporator toabout 200 ml being careful not to overheat. The residue was dissolved inabout 150 ml of ethanol.

In a separate vessel, 25.3 g (1.1 mole) of sodium was dissolved in 800ml of 200 proof ethanol under nitrogen gas sweep. After dissolution wascomplete, 83.6 g (1.1 mole) of thiolacetic acid was added slowly and theresulting solution was stirred an additional 10 min. The above preparedethanolic solution of methanesulfonate was added and the resultingsolution was heated to 60° C. for 20 hrs. The mixture was cooled to 25°C. and filtered and the filtrate was concentrated in a rotaryevaporator. The residue was dissolved in isopropyl ether and the mixturefiltered to remove a small amount of solid. The filtrate wasconcentrated and the residue distilled to yield 70 g of the free basetitle ester, b.p. 95-105/15 mm.

A 7 g portion of the free base was treated with 4 g of oxalic acid inisopropyl alcohol and the salt obtained was recrystallized fromisopropyl alcohol to give 8.4 g of title product, m.p. 108°-111° C.

PREPARATION 21 1-Methyl-3-pyrrolidinethiol oxalate

A solution of 62 g (0.39 mole) of 1-methyl-3-pyrrolidinethiol acetate(ester) in 200 ml of absolute methanol was treated with a 2 mm sphere ofsodium and the resulting solution was distilled at 1 atm. pressure to apot temperature of 100° C. Vacuum was applied and the pressure wasslowly decreased to 100 mm. The residue was distilled to a pottemperature of 130° C., yielding 25 g (56%) of distillate with a boilingpoint of 95°-100° C./100 mm which was the free base of the titlecompound. A 4 g sample was treated with oxalic and in isopropyl alcoholto give 5.5 g of oxalate salt, m.p. 80°-82° C.

PREPARATION 22 2-[(1-Methyl-3-pyrrolidinyl)thio]-3-pyridinecarboxylicacid

To a stirred suspension of 80 g (2 mole) of 60% sodium hydride (inmineral oil) in 800 ml of dry dimethylformamide, all heated to 60° C.and using nitrogen gas flow was added dropwise, a solution of 157.0 g (1mole) of 2-chloronicotinic acid and 117 g (1 mole) of1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a ratewhich maintained a temperature of 60°-67° C. The mixture was heated to65° C. for 6 hr and allowed to stand overnight at room temperature andthen filtered. The collected solid was suspended in one liter ofisopropyl alcohol and hydrogen chloride was bubbled into the suspensionuntil a pH of 6.2 was reached. The mixture was brought to a boil andfiltered. The solid was dissolved in 2 liters of water and extractedwith isopropyl ether. The pH was adjusted to 6.0 and the solution wasconcentrated to a volume of 800 ml and placed in a refrigerator. Theresulting solid (85 g) collected by filtration, was a mixture consistingof about 85% of the title compound and 15% sodium chloride. A sampleportion of this was crystallized once from ethanol and twice fromisopropyl alcohol-water. The recrystallized product decomposed at about225° C.

PREPARATION 23 Sodium 2-[(1-Cyclohexyl-3-azetidinyl)oxy]-3-pyridinecarboxylate

A solution of 105 g (0.68 mole) of 1-cyclohexyl-3-azetidinol and 106 g(0.68 mole) of 2-chloronicotinic acid in 400 ml of dry dimethylformamidewas added at a rapid drop to 52 g (1.35 mole) of 60% sodiumhydride/mineral oil suspended in 400 ml of dry dimethylformamide at 60°C. Mild exothermic reaction was noted. After stirring for 2 hr at 60°C., the mixture was filtered. The filter cake was washed withethylacetate and dried at 80° C./2 mm to give 174 g (86%) of crude titlecompound.

PREPARATION 24 2-[N-Methyl, N-(3-(1-ethylpyrrolidinyl)]-benzoic acidlithium salt

A mixture of 1068 g (6 mole) of 3-bromo-1-ethylpyrrolidine, 828 g (6mole) of potassium carbonate and 1700 ml of N-methylaniline was stirredat reflux for 2 hr, cooled and filtered. The filtrate was extracted withdilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate anddistilled. Yield of 1-ethyl-3-(N-methyl, N-phenylamino)pyrrolidine was452 g (37.5%), b.p. 100-105/0.1 mm.

The above prepared compound, 20.5 g (0.1 mole) and 46.5 g of 15.1%butyllithium and 20 ml of diethyl ether were heated at reflux for 2 hr.The reaction mixture was then poured onto a slurry of dry ice in diethylether. The excess carbon dioxide was allowed to evaporate over a periodof time and the residue was stirred in diethyl ether and filtered. Thefilter cake was dried in vacuo to give 15 g of the title product.

PREPARATION 25 2-Chloro-3-quinolinecarboxylic acid

To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml ofdry tetrahydrofuran under a continuous nitrogen blanket, at -70° C., wasadded 61.6 ml of 2.7M n-butyllithium in hexane (0.165 mole) whilemaintaining the temperature at -60° to -70° C. Subsequent to thisaddition, the temperature was maintained at -65° C. for approximately 20minutes. A solution of 20 g (0.12 mole) of 2-chloroquinoline in 60 ml oftetrahydrofuran was added dropwise while maintaining the temperature at-60° to -70° C. After holding the temperature at -65° C. for 20 minutessubsequent to this addition, the entire reaction mixture was poured ontoa large excess of dry ice. Most of the solvent was evaporated in astream of air; the residual solvent was removed by rotary evaporation.The residue was taken up in 300 ml water, made basic with dil aq. sodiumhydroxide and washed with 3×50 ml of isopropyl ether. The aqueous layerwas filtered and made acidic (4 to 5 pH) with dilute aqueoushydrochloric acid. The precipitate was collected, washed with water,isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%)of white crystals, m.p. 190°-210° C. (decomp.). A sample wasrecrystallized from isopropyl alcohol giving an analytical sample, m.p.190°-210° C. (decomp.).

Analysis: Calculated for C₁₀ H₆ NO₂ : C, 57.85; H, 2.91; N, 6.75. Found:C, 57.80; H, 2.96; N, 6.6.

PREPARATION 26 4-Chloro-7-(trifluoromethyl)-3-quinolinecarboxylic acid

To a cooled solution of 15.8 ml (0.11 mole) of diisopropyl amine in 250ml of tetrahydrofuran under a blanket of dry nitrogen at -70° C. wasadded 44 ml of 2.7M n-butyllithium in hexane at -60° to -70° C. Thesolution was stirred for 20 minutes at -70° C. and a solution/suspensionof 25 g (0.11 mole) of 3-chloro-7-trifluoromethyl quinoline in 125 ml oftetrahydrofuran was added dropwise while maintaining the temperaturebetween -60° and -70° C. The temperature was held at -70° C. for 20minutes subsequent to the addition of the quinoline. The solution (deepred) was poured onto a large excess of dry ice and the solvent allowedto evaporate overnight at room temperature. The residual solvent wasremoved by rotary evaporation (60° C., 30 mm) and the residue taken upin 800 ml of dil sodium hydroxide. An attempted wash with 75 ml ofchloroform caused the sodium salt of the product acid to precipitateout. This precipitate was collected and washed with 1 liter ofchloroform and suspended in 500 ml of water. The suspension was stirredwhile acidifying with 6N hydrochloric acid to pH 2. The solid wascollected and washed with 500 ml of water. After drying, 16.2 g (53%) ofwhite solid was collected, m.p. 310° C.

Analysis: Calculated for C₁₁ H₅ NO₂ ClF₃ : C, 47.94; H, 1.83; N, 5.08.Found: C, 47.56; H, 1.79; N, 4.99.

PREPARATION 27 3,5-Dichloro-4-pyridinecarboxylic acid

To a solution of 4.96 ml (0.036 mole) of diisopropylamine in 200 ml oftetrahydrofuran at -65° C. under a nitrogen blanket was added dropwise14.9 ml of 2.5M n-butyllithium in hexane while maintaining the abovetemperature. Twenty minutes subsequent to that addition, a solution 5.0g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60°to -70° C. was added. The reaction mixture was stirred at -70° C. for1/2 hr, poured onto a large excess of dry ice and allowed to evaporateovernight at room temperature. The residue was taken up in 100 ml ofdilute aqueous sodium hydroxide, washed with 3×30 ml ofmethylenechloride and filtered. The filtrate was acidified to ˜pH 2 withdilute hydrochloric acid to precipitate out the product. After cooling,the precipitate was collected and recrystallized from ethylacetate/hexane giving 1.9 g (29%) of white analytically pure crystals,m.p. 231°-35° C. (decomp.).

Analysis: Calculated for C₆ H₃ NO₂ Cl₂ : C, 37.53; H, 1.57; N, 7.30.Found: C, 37.33; H, 1.56; N, 7.21.

PREPARATION 28 5-Hydroxy-6-isoquinolinecarboxamide

5-Hydroxy-6-isoquinolinecarboxylic acid methyl ester as reported byDyke, S. F. et al., in Tetrahedron 1973, 29(6), 857-62, is reacted withexcess ammonia in a steel bomb for 12-18 hr. The excess ammonia isallowed to evaporate and the residue is crystallized from a suitablesolvent mix such as ethyl acetate-toluene to give the title compound.

PREPARATION 295-[(1-Methyl-3-pyrrolidinyl)oxy]-6-isoquinolinecarboxamide

Following the procedure of Preparation 10, but substituting5-hydroxy-6-isoquinolinecarboxamide for1-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.

PREPARATION 30 7-Hydroxy-6-isoquinolinecarboxamide

7-Hydroxy-5-isopuinolinecarboxylic acid methyl ester as reported by Dyke(see ref. given in Prep. 28) is reacted with excess ammonia in a steelbomb for 12-18 hr. The excess ammonia is allowed to evaporate and theresidue is crystallized from a suitable solvent mix such as ethylacetate-toluene to give the title compound.

PREPARATION 317-[(1-Methyl-3-pyrrolidinyl)oxy]-6-isoquinolinecarboxamide

Following the procedure of Preparation 10, but substituting5-hydroxy-6-isoquinolinecarboxamide for1-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.

PREPARATION 325-Methyl-8-[(1-methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide

Following the procedure of Preparation 10, but substituting8-hydroxy-5-methyl-7-quinolinecarboxamide [as reported by V-Kapoor etal, Indian J. Chem. 4(10), 438-51 (1966); (C.A. 66, 75802p)] for 1hydroxy-2-naphthalenecarboxamide, the title compound is prepared.

PREPARATION 33 8-Hydroxy-2-methyl-7-quinolinecarboxylic acid methylester

8-Hydroxy-2-methyl-7-quinolinecarboxylic acid (as reported by Meek, W.H. et al., in J. Chem. Eng. Data 1969, 14(3), 388-91) is reacted withmethanolic boron trifluoride solution for several hours. The resultingmixture is added to an aqueous solution of sodium bicarbonate to givefinally a basic solution. The solution is extracted with chloroform. Thechloroform extract is dried over anhydrous sodium sulfate andconcentrated and the residue is crystallized from a suitable solventsuch as isooctane to give the title compound.

PREPARATION 34 8-Hydroxy-2-methyl-7-quinolinecarboxamide

8-Hydroxy-2-methyl-7-quinolinecarboxylic acid methyl ester is reactedwith excess ammonia in a steel bomb for 12-18 hr. The excess ammonia isallowed to evaporate and the residue is crystallized from a suitablesolvent to give the title compound.

PREPARATION 352-Methyl-8-[(1-methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide

Following the procedure of Preparation 10, but substituting8-hydroxy-2-methyl-7-quinolinecarboxamide for1-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.

PREPARATION 36 6-Hydroxy-5-quinolinecarboxylic acid methyl ester

6-Hydroxy-5-quinolinecarboxylic acid [as reported by Da Re, P. et al. inAnn. Chem. (Rome) 1970, 60(3), 215-24 (C.A. 73, 25338m)] is reacted withmethanolic boron trifluoride solution for several hours. The resultingmixture is added to an aqueous solution of sodium bicarbonate to givefinally a basic solution. The solution is extracted with chloroform. Thechloroform extract is dried over anhydrous sodium sulfate andconcentrated and the residue is crystallized from a suitable solvent.

PREPARATION 37 6-Hydroxy-5-quinolinecarboxamide

6-Hydroxy-5-quinolinecarboxylic acid methyl ester is reacted with excessammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed toevaporate and the residue is crystallized from a suitable solvent togive the title compound.

PREPARATION 38 6-[(1-Methyl-3-pyrrolidinyl)oxy]-5-quinolinecarobxamide

Following the procedure of Preparation 10, but substituting6-hydroxy-5-quinolinecarboxamide for 1-hydroxy-2-naphthalenecarboxamide,the title compound is prepared.

PREPARATION 39 8-Hydroxy-7-quinolinecarboxamide

8-Hydroxy-7-quinolinecarboxylic acid methyl ester [as reported byEckstein, Z. et al. in Pol. J. Chem. 1979, 53(11), 2373-7 (C.A. 92,215243s)] is reacted with excess ammonia in a steel bomb for 12-18 hr.The excess ammonia is allowed to evaporate and the residue iscrystallized from a suitable solvent to give the title compound.

PREPARATION 40 8-[(1-Methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide

Folling the procedure of Preparation 10, but substituting8-hydroxy-7-quinolinecarboxamide for 1-hydroxy-2-naphthalenecarboxamide,the title compound is prepared.

PREPARATION 41 (Refer to Chart VIII)2-Chloro-N-[4-(dimethylamino)-2-hydroxybutyl]-3-pyridinecarboxamidemonohydrochloride

To a suspension of 11.9 g (0.076 mole) of 2-chloronicotinic in 200 ml ofmethylene chloride was added 10.2 g (0.076 mole) of1-hydroxybenzotriazole, 10 g (0.076 mole) of1-amino-4-(dimethylamino)-2-butanol, and 15.6 g (0.076 mole) ofdicyclohexylcarbodiimide. The resulting solution was stirred at roomtemperature for 6 hr and allowed to stand for 66 hr. The resultingmixture was filtered and the filtrate concentrated on the rotaryevaporator. The residue was shaken with a mixture of dilute hudrochloricacid and isopropyl ether. The resulting 3 phase system (1 solid, 2liquid) was filtered and the solid discarded. The aqueous layer wasseparated, made basic with sodium hydroxide and extracted 3 times withchloroform. The combined chloroform extracts were combined, dried overanhydrous sodium sulfate and concentrated. The residue was dissolved inisopropyl alcohol and acidified with ethereal hydrogen chloride. Theresulting precipitate was dissolved by heating and adding methanol. Thecrystals obtained on cooling were recrystallized from ethanol to give9.6 g (41%), m.p. 182°-192° C.

Analysis: Calculated for C₁₂ H₁₉ N₃ O₂ Cl₂ : C, 46.77; H, 6.21; N,13.63. Found: C, 46.67; H, 6.42; N, 13.91.

PREPARATION 42 (S)-3-Hydroxy-1-methyl-2,5-pyrrolidinedione

To a stirred solution of 134 g (1 mole) of (S)-malic acid in 700 ml oftoluene was added 97 ml of 40% aqueous methylamine. The temperatureslowly rose to 50° C. After 0.5 hr the stirred mixture was heated toreflux and the water was collected in a Dean-Stark trap for 48 hours. Atotal of 93 ml of water was collected. The toluene residue was treatedwith 300 ml of ethanol and concentrated on the rotary evaportor. Theresidue was distilled. The yield of product obtained was 101 g (78%),b.p. 140°/2 mm; 145°/0.5 mm.

A sample of the above compound was crystallized from ethylacetate-isopropyl ether, m.p. 87°-89° C.; [α]_(D) ²⁵ =-79.2 (methanol).

Analysis: Calculated for C₅ H₇ NO₃ : C, 46.51; H, 5.46; N, 10.84. Found:C, 46.77; H, 5.55; N, 11.03.

PREPARATION 43 (S)-1-Methyl-3-pyrrolidinol-(2S,3S)-tartrate [1:1]

A solution of 25.3 g (0.2 mole) of(S)-3-hydroxy-1-methyl-2,5-pyrrolidinedione in 150 ml of tetrahydrofuranwas added dropwise so as to maintain reflux to a stirred solution of 226g (0.78 mole) of Red-al (bis(methoxyethoxy)sodium aluminum hydride) in500 ml of tetrahydrofuran. The refluxing was continued 1 hr afteraddition was complete. The solution was cooled with an ice bath and 30ml of water was added dropwise followed by 30 ml of 15% sodium hydroxidewhich was followed by 90 ml of water. The resulting mixture was heatedto reflux for 0.5 hr, cooled to 30° C. and the layers separated. Theaqueous layer was extracted 5 times with chloroform. The organic layerswere combined, dried over sodium sulfate and concentrated. The residuewas distilled. Yield of product was 13 g (64%) b.p. 95°-100° C./90 mm.[α]_(D) ²⁵ =+0.794 (neat). 1 gram of the liquid was treated with 1.5 g(25,35) tartaric acid in methanol. The resulting crystals weighed 2 g,m.p. 129°-131° C. [α]_(D) ²⁵ =-11.5 (water).

Analysis: Calculated for C₉ H₁₇ NO₇ : C, 43.02; H, 6.82; N, 5.57. Found:C, 42.98; H, 6.87; N, 5.55.

PREPARATION 44 (S)-1-Methyl-3-pyrrolidinol (2S,3S)-tartrate [1:1]

To a solution of 420 g (4.16 mole) of racemic mixture of1-methyl-3-pyrrolidinol in 1 liter of dry methanol cooled in an ice bathwas added 500 g (3.33 mole) of (2S,3S) tartaric acid dissolved in 1liter of methanol. At 50° C. the solution was seeded with crystalsobtained in Preparation 43. The resulting crystals were collected byfiltration and and recrystallized three times with methanol to give 235g (45%) of analytically pure white crystals, m.p. 125°-129° C. [α]_(D)²⁵ =(-) 11.6 (water).

Analysis: Calculated for C₉ H₁₇ NO₇ : C, 43.02; H, 6.82; N, 5.57. Found:C, 42.75; H, 6.87; N, 5.46.

PREPARATION 45 (S)-1-Methyl-3-pyrrolidinol

A 235 g sample of (S)-1-methyl-3-pyrrolidinol (2S,3S) tartrate [1:1] wastreated with 135 g of potassium hydroxide in 200 ml of water and thesolution was continuously extracted with chloroform for 24 hr. Tjechloroform solution was dried over sodium sulfate, concentrated anddistilled. Yield of product was 80 g, b.p. 103-106/37-40 mm; [α]_(D) ²⁵=+0.817° (neat).

Analysis: Calculated for C₅ H₁₁ NO: C, 59.37; H, 10.96; N, 13.85. Found:C, 57.64; H, 10.40; N, 13.47.

PREPARATION 46 (R)-1-Methyl-3-pyrrolidinol (2R,3R)-tartrate [1:1]

To a solution of 420 g (4.16 mole) of 1-methyl-3-pyrrolidinol in 1 literof dry methanol cooled in an ice bath was added 500 g (3.33 mole) of-(2S,3S) tartaric acid dissolved in 1 liter of methanol. At 50° C. thesolution was seeded with (S)-1-methyl-3-pyrrolidinol-(2S,3S)-tartrate[1:1]. The resulting crystals were collected by filtration and theorganic layer was concentrated. The residue was partitioned betweendilute sodium hydroxide and chloroform and the aqueous layer extractedby continuous extraction with chloroform for 24 hr. The organic layerswere combined, dried over sodium sulfate and concentrated. The residuewas dissolved in 500 ml of methanol and to this solution was added150.09 g (1 mole) of (2R,3R) tartaric acid dissolved in 500 ml ofmethanol. The mixture was filtered and the solid recrystallized twotimes from methanol to give 75.2 g, (14%) of analytically pure whitecrystals, m.p. 124°-127° C.; [α]_(D) ²⁵ =(+) 11.1 (water).

Analysis: Calculated for C₉ H₁₇ NO₇ : C, 43.02; H, 6.82; N, 5.57. Found:C, 42.84; H, 6.91; N, 5.63.

PREPARATION 47 (R)-1-Methyl-3-pyrrolidinol

A 200 g sample of (R)-1-methyl-3-pyrrolidinol-(2R,3R) tartrate [1:1] wastreated with 135 g of potassium hydroxide and the resulting solutioncontinuously extracted with chloroform for 24 hr. The chloroform extractwas dried over anhydrous sodium sulfate, concentrated and distilled.Yield of product was 73 g, b.p. 103-106/35 mm, [α]_(D) ²⁵ =-0.852°(neat).

Analysis: Calculated for C₅ H₁₁ NO: C, 59.37; H, 10.96; N, 13.85. Found:C, 57.71; H, 10.78; N, 13.49.

PREPARATION 48 5-Bromo-2-chloro-3-pyridinecarboxylic acid

To 15 g (0.069 mole) of 5-bromo-2-hydroxy nicotinic acid was added 75 mlof thionyl chloride and 3 ml of dimethylformamide. The mixture washeated to reflux for 30 minutes. After cooling, the excess thionylchloride was removed by rotary evaporation and the residue poured intowater (1 liter) with vigorous agitation. The precipitate was collectedand the mother liquor condensed to 1/2 the volume, yielding additionalprecipitate. The precipitates were combined and crystallized fromtoluene giving 6 g (37%) of material. The product was recrystallizedfrom toluene, m.p. 174°-177° C.

Analysis: Calculated for C₆ H₃ NO₂ ClBr: C, 30.48; H, 1.28; N, 5.92.Found: C, 30.21; H, 1.25; N, 5.89.

PREPARATION 49 5-Bromo-2-hydroxy-3-pyridinecarboxylic acid

To a solution of 10 g (0.07 mole) of 2-hydroxy-nicotinic acid in 16.8 gof 50% sodium hydroxide (0.21 mole) diluted with 25 ml of water wasadded 200 ml of sodium hypobromite solution prepared by adding 13.6 g(0.17 mole) of bromine to a solution of 20.16 g of 50% sodium hydroxide(0.25 mole) in 125 ml of water at 0° C. diluted to 400 ml. After 24 hrsof stirring at room temperature, another 100 ml portion of the abovesodium hypobromite solution was added and the reaction solution wasstirred for another 24 hr. The reaction solution was cooled in an icebath and acidified carefully with 12N hydrochloric acid. Crystallizationfrom isopropyl alcohol gave 9.7 g (63.5%) of product. A sample wasfurther recrystallized from 95% ethanol, m.p. 245° C.

Analysis: Calculated for C₆ H₄ NO₃ : C, 33.06; H, 1.85; N, 6.42. Found:C, 32.98; H, 1.83; N, 6.44.

PREPARATION 50 2-(1-Methyl-3-pyrrolidinyloxy)-5-nitrobenzamide

To a cooled suspension of sodium hydride (2.42 g of 60% content 0.06mole) in 50 ml of dimethylformamide under nitrogen was added dropwise asolution of 10 g (0.055 mole) of 2-chloro-5-nitrobenzamide in 20 mldimethylformamide. The suspension was stirred at room temperature for 1hr and heated to 60° C. at which time 9.9 g (0.055 mole) ofN-methyl-3-pyrrolidinylmesylate (freshly prepared) in 10 ml ofdimethylformamide was added. The reaction mixture was heated to 135° C.for 24 hr. Since little product was observed, 9.9 g (0.055 mole)addition N-methyl-3-pyrrolidinylmesylate and 1.21 g (60% in oil, 0.03mole) of sodium hydride was added. Heating was continued for 24 hr.Another 4 equivalents of the above mesylate was added after cooling thereaction mixture to 100° C. The reaction mixture was maintained at 100°C. for 24 hr. The dimethylformamide was removed by rotary evaporation at60° C., 0.5 mm Hg. The residue was taken up in 400 ml of methylenechloride and washed with 3×200 ml of 1N sodium hydroxide and 2×200 mlwater. The organic layer was extracted with 3×200 ml of 1N hydrochloricacid. The aqueous extracts were combined and washed with ˜200 mlchloroform. The aqueous layer was made basic with concentrated sodiumhydroxide and extracted with 2×300 ml of methylene chloride. The organicextracts were combined, dried over sodium sulfate, filtered, andconcentrated by rotary evaporation. The residue was crystallized fromtoluene to give 1.7 g (12%) of crude crystals. One recrystallizationfrom toluene afforded light beige crystals, m.p. 215°-10° C.

Analysis: Calculated for C₁₂ H₁₅ N₃ O₄ : C, 54.34; H, 5.70; N, 15.84.Found: C, 54.30; H, 5.73; N, 15.80.

PREPARATION 51 5-Fluoro-2-(1-methyl-3-pyrrolidinyloxy)benzamide

To a suspension of 0.44 g (60% in oil, 0.011 mole) of sodium hydride in10 ml of dimethylformamide was added 1.55 g (0.01 mole) of5-fluoro-2-hydroxybenzamide in 10 ml of dimethylformamide under nitrogenatmosphere at room temperature. The reaction mixture was heated to 60°C. and 1.80 g (0.01 mole) of 1-methyl-3-pyrrolidinol methane sulfonate(ester) was added. The reaction mixture was then heated to 100° C. for18 hr. The dimethylformamide was removed by rotary evaporation at 70°C., 0.5 mm Hg. The residue was taken up in 200 ml of methylene chloride,washed with 2×50 ml of 1N sodium hydroxide and 50 ml of water. Theorganic phase was extracted with 2×50 ml of 1N hydrochloric acid. Thecombined aqueous extracts were washed with 50 ml of methylene chloride,made basic with concentrated sodium hydroxide and extracted into 2×50 mlof methylene chloride. The combined organic extracts were dried oversodium sulfate, filtered and concentrated by rotary evaporation. Theresidual oil was crystallized from hexane to give 1.0 g of off-whitecrystals. m.p. 90°-93° C.

Analysis: Calculated for C₁₄ H₁₅ N₂ O₂ F: C, 60.49; H, 6.35; N, 11.76.Found: C, 60.47; H, 6.39; N, 11.75.

INTERMEDIATE 12-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one

To 54 g (1.35 mole) of sodium hydroxide in 800 ml of water was added 148g (0.67 mole) of 2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and themixture brought to reflux for 18 hr. The pH was adjusted to 7 withhydrochloric acid and the solution filtered and concentrated. Theresidue was boiled with 400 ml of isopropanol and filtered. The filtratewas concentrated and the residue (which crystallized) was refluxed with300 ml of thionyl chloride for 0.5 hr. and concentrated in vacuo. Theresidue was dissolved in 300 ml of chloroform and the solvent boiled offin vacuo. The residue was redissolved in chloroform, 150 ml of triethylamine added and the mixture refluxed 1 hr. The solution was concentratedin vacuo and the residue partitioned between 400 ml of ethyl acetate,400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. Theorganic layer was washed twice with water and once with dilute sodiumhydroxide, dried with sodium sulfate and concentrated. The residue wascrystallized from isopropanol-water. Yield of product was 75 g (47%),m.p. 97°-107° C.

Analysis: Calculated for C₁₂ H₁₄ NO₂ Cl: C, 60.13; H, 5.89; N, 5.84.Found: C, 60.35; H, 5.91; N, 5.65.

INTERMEDIATE 24-Benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one

To 85.7 g (0.29 mole) of 2-[(1-benzyl-3-pyrrolidinyl)oxy]-benzoic acidwas added 150 ml of thionyl chloride. The solution stood for 15 min andwas then refluxed 30 min. and concentrated in vacuo. The residue wastwice treated with 250 ml of chloroform and concentrated in vacuo. Theresidue was dissolved in 500 ml of chloroform and 101 g (1 mole) oftriethylamine added slowly with stirring. The solution was refluxed 1hr. and concentrated in vacuo. The residue was partitioned between 50%ethyl acetate-50% isopropyl ether and dilute hydrochloric acid. Theorganic layer was washed with dilute sodium hydroxide and concentrated.The residue was crystallized 5 times from isopropyl ether-ethyl acetate.Yield of product was 23.8 g (26%), m.p. 145.0°-147° C.

Analysis: Calculated for C₁₈ H₁₈ NO₂ Cl: C, 68.46; H, 5.74; N, 4.44.Found: C, 68.47; H, 5.89; N, 4.32.

INTERMEDIATE 32-(2-(Chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepin-5(4H)-one

To a solution of 21.6 g (0.54 mole) sodium hydroxide in 500 ml of waterwas added 74 g (0.27 mole) of3-[1-methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxamide and the mixtureheated at reflux for 16 hr. The pH was adjusted to 6.8 with concentratedhydrochloric acid, the solution was filtered and concentrated. Theresidue was boiled with 200 ml of isopropyl alcohol and filtered. Thefiltrate was concentrated under reduced pressure and the residuedissolved in chloroform. Thionyl chloride (59 g, 0.50 mole) was addedand the reaction mixture heated at reflux for 4 hr. After cooling (67 g,0.67 mole) triethylamine was added dropwise. The mixture was washedsequentially; twice with 3N hydrochloric acid, twice with water, twicewith 10% sodium hydroxide, twice with water and dried over magnesiumsulfate. Evaporation of the chloroform under reduced pressure gave 44 g(58%) of a viscous dark brown oil. The material was purified by highpressure liquid chromatography (50/50 ethyl acetate/hexane) andrecrystallized from isopropyl alcohol to yield brown crystals,m.p.=101°-102° C.

Analysis: Calculated for C₁₆ H₁₆ NClO₂ : C, 66.32; H, 5.57; N, 4.83.Found: C, 66.19; H, 5.63; N, 4.77.

INTERMEDIATE 42-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride

Hydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mole)of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate in 1liter of chloroform until a pH of 6 was reached. To the stirred mixturewas added 350 g (1.34 mole) of triphenylphosphine and 350 g (2.3 mole)of carbon tetrachloride and the resulting cloudy solution was stirred atreflux for 1.5 hr. About 100 ml of ethanol was added and the heatremoved. The solution was stirred for 1 hour while cooling and 200 ml ofisooctane was added. The solution was extracted 4 times with a total of800 ml of dilute hydrochloric acid. The acid extracts were combined,made basic with sodium hydroxide and extracted with chloroform. Thechloroform layer was separated and dried over sodium sulfate andconcentrated. The residue was dissolved in a mixture of 500 ml each ofisopropyl alcohol and isopropyl ether and acidified with etherealhydrogen chloride. The resulting crystals weighed 82 g (49%). A portionwas recrystallized from isopropyl alcohol, m.p. 149°-153° C.

Analysis: Calculated for C₁₁ H₁₄ N₂ O₂ Cl₂ : C, 47.67; H, 5.09; N,10.11. Found: C, 47.57; H, 5.18; N, 10.00.

INTERMEDIATE 58-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one

To a solution of 10.4 g (0.26 mole) of sodium hydroxide in 150 ml ofwater was added 32 g (0.13 mole) of4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture washeated at reflux for 24 hr. The reaction mixture was adjusted to pH 6with concentrated hydrochloric acid and filtered and the filtrateconcentrated. The residue was boiled with 100 ml of isopropyl alcoholand the mixture filtered. The filtrate was concentrated and heated atreflux with 98 g (b 0.83 mole) of thionyl chloride for 1 hr. The excessthionyl chloride was evaporated under reduced pressure. The residue wasdissolved in 70 ml of chloroform and the solvent evaporated underreduced pressure. The residue was redissolved in 75 ml of chloroform and40 ml of triethylamine was added gradually. The mixture was heated atreflux for 1 hr. The solvent was evaporated under reduced pressure togive a dark-brown solid. The solid was dissolved in ethyl acetate andthe resulting solution washed twice with 200 ml of water and twice with250 ml of 20% sodium hydroxide. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure to give 21 g(59%) of dark-brown solid. The solid was recrystallized from isopropylalcohol to give the title compound, m.p. 85°-87° C.

Analysis: Calculated for C₁₂ H₁₃ NCl₂ O₂ : C, 52.57; H, 4.78; N, 5.11.Found: C, 52.57; H, 4.77; N, 5.04.

INTERMEDIATE 67-Bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one

To a solution of 9.6 g (0.24 mole) of sodium hydroxide in 200 ml ofwater was added 37 g (0.12 mole) of5-bromo-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture washeated at reflux for 18 hr. The pH of the mixture was adjusted to 6.7with concentrated hydrochloric acid solution. The solution wasconcentrated under reduced pressure and the residue was boiled in 250 mlof isopropyl alcohol for 1 hr. The mixture was filtered and the filtratewas concentrated. The residue was dissolved in chloroform and to thesolution was added 28.3 g (0.24 mole) of thionyl chloride. The mixturewas heated at reflux for 0.5 hr and cooled to 15° C. with an ice bath.To the mixture was added dropwise 26.6 g (0.26 mole) of triethylamine atsuch a rate that the temperature did not exceed 25° C. The reactionmixture was stirred at room temperature for 1 hr, then washedconsecutively with 3N hydrochloric acid, 15% aqueous sodium hydroxideand water. The chloroform layer was dried over magnesium sulfate andconcentrated under reduced pressure to give 23 g (60%) of brown solid. Aportion of the solid was recrystallized from ethyl acetate-isopropylether, m.p. 92°-94° C.

Analysis: Calculated for C₁₂ H₁₃ NBrClO₂ : C, 45.24; H, 4.11 N, 4.40.Found: C, 45.61; H, 4.17; N, 4.42.

INTERMEDIATE 77-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one

Hydrogen chloride was bubbled through a solution of 113 g (0.44 mole)5-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide dissolved in 500 mlof glacial acetic acid for 15 min while the reaction was cooled with anice bath. Butylnitrite (142 g, 1.38 mole) was then added in one portion;the reaction was stirred at room temperature for 16 hr and heated atreflux for an additional 6 hr. The acetic acid was evaporated underreduced pressure, tetrachloroethane was added twice to the residue andevaporated.

The residue was dissolved in chloroform, treated with 163 g (1.38 mole)of thionyl chloride and heated at reflux for 22 hr. The reaction mixturewas cooled with an ice bath and 152 g (1.5 mole) of triethylamine wasadded dropwise at such a rate that the temperature was kept at 25°-30°C. The reaction mixture was diluted with 200 ml of chloroform and washedconsecutively with 3N hydrochloric acid, water, 10% sodium hydroxide andwater. The chloroform was evaporated under reduced pressure to give 40 gof a black, tar-like residue (33%).

An aliquot of this residue was purified on a silica gel column usingethyl acetate as the eluting solvent. Recrystallization from isopropylalcohol gave beige crystals, m.p. 101°-103° C.

Analysis: Calculated for C₁₂ H₁₃ NCl₂ O₂ : C, 52.57; H, 4.78; N, 5.11.Found: C, 52.63; H, 4.83; N, 5.05.

INTERMEDIATE 82-[(2-Chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-one

Hydrogen chloride gas was bubbled into a solution of 8 g (0.03 mole) of1-[(1-methyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxamide in 40 ml ofacetic acid for about 2 min. The solution was cooled with an ice bathand 6.1 g (0.06 mol) of n-butyl nitrite was added slowly beneath thesurface of the liquid at 12°-15° C. (about 10 minutes required). Thesolution was stirred at 25° C. for 18 hr and heated on the steam bathfor 3 hr. The solution was concentrated on the rotary evaporator. Theresidue was dissolved in 60 ml of 1,1,2,2-tetrachloroethane which wasremoved on the rotary evaporator at 0.5 mm/steam temperature.

The residue was dissolved in 75 ml of chloroform and treated with 7 g(0.06 mole) of thionyl chloride and brought to reflux for 12 hr. Thesolution was extracted with water (tested acidic) followed by dilutesodium hydroxide, dried over sodium sulfate and concentrated. Theresidue was crystallized twice from isopropyl etherethyl acetate. Yieldof product was 3.2 g (37%), m.p. 109°-111° C.

Analysis: Calculated for C₁₆ H₁₆ NO₂ Cl: C, 66.32; H, 5.57; N, 4.84.Found: C, 66.15; H, 5.56; N, 4.76.

INTERMEDIATE 92-(2-Chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-one

To a solution of 19.2 g (0.48 mole) of sodium hydroxide in 500 ml ofwater was added 60 g (0.24 mole) of5-methoxy-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture washeated at reflux for 24 hr. The reaction mixture was cooled and the pHadjusted to 6.8 with concentrated hydrochloric acid. The mixture wasconcentrated under reduced pressure and the residue was boiled inisopropyl alcohol for 1 hour. The mixture was filtered and the filtratewas concentrated. The residue was dissolved in 500 ml of chloroform andto this solution was added 114 g (0.96 mole) of thionyl chloride. Themixture was heated at reflux for 48 hr, then cooled with an ice/acetonebath. To the mixture was added dropwise 97 g (0.96 mole) oftriethylamine at such a rate that the temperature did not exceed 25° C.The reaction solution was washeed in sequence with water, 3Nhydrochloric acid solution, water, 15% aqueous sodium hydroxide andwater and finally dried over magnesium sulfate. The solvent wasevaporated under reduced pressure to give a black solid. The solid waspurified on a silica gel column using ethyl acetate as the elutingsolvent to give on isolation 15 g (23%) of beige colored product, m.p.98°-100° C.

Analysis: Calculated for C₁₃ H₁₆ NClO₃ : C, 57.89; H, 5.98; N, 5.19.Found: C, 57.53; H, 6.00; N, 5.16.

INTERMEDIATE 102-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione

A mixture of 18.5 g (0.0834 mole) of phosphorus pentasulfide and 18.5 gpotassium sulfide was ground together and added to a solution of 100 g(0.417 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in drytoluene, the mixture refluxed 24 hr. and filtered. The filtrate wasconcentrated and partitioned between chloroform and diluted sodiumhydroxide. The chloroform layer was concentrated and the residue wascrystallized several times from ethanol. Yield of product was 55 g(52%), m.p. 105°-108° C.

Analysis: Calculated for C₁₂ H₁₄ NSOCl: C, 56.35; H, 5.52; N, 5.48; S,12.54. Found: C, 56.55; H, 5.47; N, 5.49; S, 12.55.

INTERMEDIATE 112-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione

To a solution of 59 g (0.25 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)onehydrochloride in 1500 ml of chloroform was added 41.5 g (0.19 mole) ofphosphorus pentasulfide and the mixture was heated to reflux for 18 hr.The mixture was filtered and the filtrate was extracted with dilutesodium hydroxide. The chloroform layer was concentrated and the residuewas dissolved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g(44%) of yellow solid precipitated. A portion was recrystallized fromisopropyl alcohol, m.p. 134°-136° C.

Analysis: Calculated for C₁₁ H₁₃ N₂ ClOS: C, 51.46; H, 5.10; N, 10.81.Found: C, 51.35; H, 5.21; N, 10.72.

INTERMEDIATE 122-(2-Chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepine-5(4H)-thione

To a solution of 16.6 g (0.06 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepin-5(4H)-onein 150 ml of dry toluene was added a mixture of 8.6 g (0.045 mole) ofphosphorus pentasulfide and 8.6 g of potassium sulfide which had beenground together. The reaction mixture was stirred and heated at refluxfor 24 hr. The mixture was filtered hot and the filtrate concentratedunder reduced pressure. Yellow solid, 6.5 g (35%) was obtained which wasrecrystallized from ethanol, m.p. 166°-168° C.

Analysis: Calculated for C₁₆ H₁₆ NClOS: C, 62.84; H, 5.27; N, 4.58.Found: C, 62.29; H, 5.48; N, 4.47.

INTERMEDIATE 138-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione

To a solution of 43 g (0.16 mole) of8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 400 ml of dry toluene was added a mixture of 23 g (0.12 mole) ofphosphorus pentasulfide and 23 g of potassium sulfide which had beenground together. The reaction mixture was stirred and heated at refluxfor 24 hr. The mixture was filtered hot and the filtrate concentratedunder reduced pressure to give 25.5 g (55%) of orange oil whichsolidified on standing at room temperature. The solid was recrystallizedfrom ethanol, m.p. 105°-106° C.

Analysis: Calculated for C₁₂ H₁₃ NCl₂ OS: C, 49.66; H, 4.52; N, 4.83.Found: C, 49.63; H, 4.53; N, 4.75.

INTERMEDIATE 147-Bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione

To a solution of 11.0 g (0.035 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 150 ml of dry toluene was added a mixture of 13.4 g (0.07 mole) ofphosphorus pentasulfide and 13.4 g of potassium sulfide which had beenground together. The reaction mixture was heated at reflux for 5 hrunder a nitrogen atmosphere. The mixture was filtered hot and thefiltrate concentrated under reduced pressure. The residue was dissolvedin chloroform. The chloroform solution was washed twice with diluteaqueous sodium hydroxide, dried over magnesium sulfate and concentratedunder reduced pressure to give 8.5 g (72%) of yellow solid. The solidwas recrystallized from ethanol, m.p. 118°-120° C.

Analysis: Calculated for C₁₂ H₁₃ NBrClOS: C, 43.07; H, 3.92; N, 4.18.Found: C, 43.08; H, 3.88; N, 4.12.

INTERMEDIATE 152-(2-Chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepine-5(4H)-thione

A mixture of 9.55 g of phosphorus pentasulfide and 9.5 g of potassiumsulfide were ground together and added to a solution of 20.2 g (0.07mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-onein 200 ml of dry toluene. The mixture was stirred and heated at refluxfor 7 hr. The hot reaction mixture was filtered and the productcrystallized from the cooled filtrate. Recrystallization from chloroformgave 18 g (84%) of yellow crystals, m.p. 167°-170° C.

Analysis: Calculated for C₁₆ H₁₆ NClOS: C, 62.84; H, 5.27; N, 4.58.Found: C, 62.85; H, 5.20; N, 4.55.

INTERMEDIATE 162-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-onehydrochloride

A 49 g (0.11 mole) sample of3-[(1-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile fumarate [1:2]was partitioned between chloroform and a saturated solution of potassiumcarbonate. The aqueous layer was extracted twice with chloroform. Allchloroform extracts were combined, dried and concentrated. The residuewas dissolved in 125 ml of t-butanol and added to 34 g (0.6 mole) ofpotassium hydroxide pellets. The mixture was stirred at room temperaturefor 88 hr. and then diluted withe 150 ml of toluene. This mixture wasfiltered and the filtrate concentrated. The residue was dissolved inchloroform, with cooling, and the pH adjusted to 6.0 with hydrogenchloride gas. The resulting mixture was concentrated and 400 ml of drytoluene was added to the residue. The toluene was removed on the rotaryevaporator (steam heat/reduced pressure) to remove any water. Theresidue was dissolved in 400 ml of chloroform and 63 g oftriphenylphosphine was added followed by 70 g of carbon tetrachloride.The solution was stirred at reflux for 2 hr and another 30 g oftriphenylphosphine added. After an additional hour reflux, 70 g morecarbon tetrachloride and 63 g more of triphenylphosphine were added andreflux was continued for 4 hr. The solution was extracted with dilutesodium hydroxide, then concentrated. The residue was partitioned betweentoluene and dilute hydrochloric acid. The toluene layer was extractedfive times with dilute hydrochloric acid. The acid extracts werecombined, basified with sodium hydroxide and extracted with chloroform.The chloroform layer was dried over sodium sulfate and concentrated. Theresidue was chromatographed on a 7×25 cm column of silica gel withacetone liquid phase. Free base of the title compound isolated afterevaporation amounted to 5.8 g (20%). To a portion of the free basedissolved in isopropyl alcohol was added ethereal hydrogen chloride andisopropyl ether. The resulting crystals were collected and dried, m.p.188°-190° C.

Analysis: Calculated for C₁₁ H₁₄ N₂ O₂ Cl₂ : C, 47.67; H, 5.09; N,10.11. Found: C, 48.33; H, 5.22; N, 9.73.

INTERMEDIATE 172-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-onehydrochloride

In the procedure of Intermediate 4, equal molar amounts of sodium4-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate was substitutedfor 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylic acid and thetitle compound was obtained.

INTERMEDIATE 182-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[2,3-f][1,4]oxazepin-5(4H)-onehydrochloride

The procedure of Intermediate 16,3-[(1-methyl-3-pyrrolidinyl)oxy]-2-pyridinecarbonitrile fumarate issubstituted for 3-[(1-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrilefumarate, the title compound is obtained.

INTERMEDIATE 197-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione

To a solution of 20 g (0.07 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 200 ml of toluene was added a mixture of 9.55 g (0.05 mole) ofphosphorus pentasulfide and 9.5 g of potassium sulfide which had beenground together. The reaction mixture was filtered and the filtrateconcentrated under reduced pressure to give a yellow solid.Recrystallization from absolute ethanol gave 12.5 g (68%) of theproduct, m.p. 102°-104° C.

Analysis: Calculated for C₁₂ H₁₃ NCl₂ OS: C, 49.66; H, 4.52; N, 4.83.Found: C, 49.62; H, 4.55; N, 4.76.

INTERMEDIATE 202-(2-Chloroethyl)-7,9-diiodo-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-on

When in the procedure of Intermediate 1,3,5-diido-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide is substituted for2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide, the title compound isprepared.

INTERMEDIATE 212-Chloromethyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-hydrochloride

When in the procedure of Intermediate 4, an equal molar amount of sodium2-[(1-methyl-3-azetidinyl)oxy]-3-pyridinecarboxylate sodium acetate issubstituted for sodium2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate, the titlecompound is prepared.

INTERMEDIATE 222-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]oxazepine-5(4H)-thione

A solution of 5 g (0.021 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-oneand 5.1 g (0.0126 mole) of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiodiphosphetane-2,4-disulfide in100 ml of dry toluene was stirred at reflux for 2.5 hr. The solution wascooled and extracted three times with sodium bicarbonate solution. Thetoluene layer was dried over sodium sulfate and concentrated. Theresidue was chromatographed (high pressure liquid chromatograph) using asilica column and ethyl acetate liquid phase. The fraction containingthe product was concentrated by evaporation and the residue wascrystallized from ethyl alcohol to give 0.6 g (11%) of the titlecompound.

INTERMEDIATE 232-(2-Chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepine-5(4H)-thione

To a solution of 10.3 g (0.04 mole) of2-(2-chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-onein 200 ml of chloroform was added a mixture of 5.7 g (0.03 mole) ofphosphorus pentasulfide and 5.7 g of potassium sulfide which had beenground together. The reaction mixture was stirred and heated at refluxunder nitrogen atmosphere for 5 hr. The mixture was filtered hot and thefiltrate concentrated under reduced pressure. The residue, an orangesolid, was recrystallized from ethanol to give 7.4 g (65%) of product,m.p. 98°-100° C.

Analysis: Calculated for C₁₃ H₁₆ NClO₂ S: C, 54.64; H, 5.65; N, 4.90.Found: C, 54.57; H, 5.67; N, 4.85.

INTERMEDIATE 24

When in the procedure of Intermediate 2, equal molar amounts of thefollowing are substituted for 2-(1-benzyl-3-pyrrolidinyloxy)benzoicacid:

2-[(1-cyclohexyl-3-pyrrolidinyl)oxy]benzoic acid,

2-[(1-ethyl-3-pyrrolidinyl)oxy]benzoic acid,

2-[(1-isopropyl-3-pyrrolidinyl)oxy]benzoic acid,

2-[[(1-(4-chlorobenzyl)-3-pyrrolidinyl]oxy]benzoic acid,

2-[[1-(4-methylbenzyl)-3-pyrrolidinyl]oxy]benzoic acid,

2-[[1-(3,5-dimethoxybenzyl)-3-pyrrolidinyl]oxy]benzoic acid,

2-[[1-(trifluoromethylbenzyl)-3-pyrrolidinyl]oxy]benzoic acid, and

2-[[1-(4-nitrobenzyl)-3-pyrrolidinyl]oxy]benzoic acid, and there areobtained:

(a)2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-1,4-benzoxazepin-5(4H)-one,

(b) 2-(2-chloroethyl)-2,3-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-one,

(c)2-(2-chloroethyl)-2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5(4H)-one,

(d)2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one,

(e)2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)-1,4-benzoxazepin-5(4H)-one,

(f)2-(2-chloroethyl)-2,3-dihydro-4-(3,5-dimethoxybenzyl)-1,4-benzoxazepin-5(4H)-one,

(g)2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)-1,4-benzoxazepin-5(4H)-one,

(h)2-(2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)-one

INTERMEDIATE 25

When in the procedure of Intermediate 4, equal molar amounts of thefollowing are substituted for sodium2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate:

2-[(1-cyclohexyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate,

2-[(1-ethyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate,

2-[1-isopropyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate,

2-[[1-(4-chlorobenzyl)-3-pyrrolidinyl]oxy]-3-pyridine carboxylate,

2- [[1-(4-methylbenzyl)-3-pyrrolidinyl]oxy]-3-pyridine carboxylate,

2-[[1-(4-methoxybenzyl)-3-pyrrolidinyl]oxy]-3-pyridine carboxylate,

2-[[1-(3-trifluoromethylbenzyl)-3-pyrrolidinyl]oxy]-3-pyridinecarboxylate, and

2-[[1-(4-nitrobenzyl)-3-pyrrolidinyl]oxy]-3-pyridine carboxylate,

there are obtained:

(a) 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-pyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride,

(b)2-(2-chloroethyl)-2,3-dihydro-4-ethylpyrido[3,2-f][1,4]-oxazepin-5(4H)onehydrochloride,

(c)2-(2-chloroethyl)-2,3-dihydro-4-isopropylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

(d)2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydropyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

(e)2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

(f)2-(2-chloroethyl)-2,3-dihydro-4-(4-methoxybenzyl)pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

(g)2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)pyrido[3,2-f][1,4]-5(4H)-onehydrochloride, and

(h)2-(2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)pyrido)[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride.

INTERMEDIATE 262-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepin-5(4H)-one

A mixture of 80.75 g (0.34 mole) of2-[(1-methyl-3-pyrrolidinyl)thio]-3-pyridinecarboxylic acid, 500 ml ofchloroform, 200 g of carbon tetrachloride and 178 g (0.68 mole) oftriphenylphosphine was stirred at reflux for 2.5 hr. The resultingsolution was extracted with one 500 ml and three 125 ml portions of 1Nhydrochloric acid. The acid extracts were combined and extracted withisopropyl ether. The aqueous layer was basified with sodium hydroxideand extracted three times with chloroform. The combined chloroformextract was dried over sodium sulfate and concentrated. A portion of theresidue was chromatographed on the high pressure liquid chromatographusing a silica column and ethyl acetate. The compound obtained wascrystallized from isopropyl ether-isopropyl alcohol, m.p. 97°-100° C.

Analysis: Calculated for C₁₁ H₁₃ N₂ OSCl: C, 51.46; H, 5.10; N, 10.91.Found: C, 51.63; H, 5.12; N, 10.85.

INTERMEDIATE 272-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepine-5(4H)-thione

A mixture of 4.3 g (0.017 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepin-5(4H)-one,100 ml of toluene and 4.8 g (0.012 mole) of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide wasrefluxed for 3 hr and then extracted twice with dilute sodium hydroxide.The organic layer was concentrated and the residue chromatographed onthe high pressure liquid chromatograph using a silica column and 50%ethyl acetate-50% hexane. The yield of title compound was 2 g, m.p.160°-162° C.

Analysis: Calculated for C₁₁ H₁₃ N₂ S₂ Cl: C, 48.43; H, 4.80; N, 10.27.Found: C, 48.46; H, 4.81; N, 10.51.

INTERMEDIATE 282-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one

A solution of 78 g (0.5 mole) of 4-chloronicotinic acid and 52 g (0.52mole) of 1-methylpyrrolidinol in 150 ml of dimethylformamide was addedto a suspension of 44 g (1.1 mole) of 60% sodium hydride/mineral oil in800 ml of dimethylformamide at a rate so as to maintain a temperature of55°-70° C. (preheated to 55° C.). The resulting mixture was heated to60° C. for 4 hr and filtered while hot. The filtrate was concentrated onthe rotary evaporator (5 mm/steam bath). The residue was dissolved in600 ml of water and extracted with isopropyl ether. The pH of theaqueous layer was adjusted to 6 with hydrochloric acid and the solutionwas concentrated on the rotary evaporator (5 mm/steam bath). The residuewas suspended in 800 ml of chloroform and 188 g (1.1 mole) oftriphenylphosphine added followed by 250 ml of carbon tetrachloride. Themixture was gently heated to 60° C. whereupon the reaction becameexothermic and an ice bath was used to maintain a temperature of 60°-65°C. for about 20 minutes. The ice bath was removed and the mixture washeated to reflux for 3.5 hr and cooled. The solution was extracted with600 ml of water followed by two 200 ml portions of 1N hydrochloric acid.The acid layer was made basic with sodium hydroxide and extracted threetimes with chloroform. The chloroform was concentrated and the residuewas chromatographed by high pressure liquid chromatography using silicagel and eluting with ethyl acetate. Yield of product was 30 g (25%). Themass spectra and NMR are in agreement with the structure of the titlecompound.

INTERMEDIATE 292-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepine-5(4H)-thionemonohydrochloride

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one,15 g (0.06 mole), was dissolved in 200 ml of dry toluene and 15 g (0.037mole) of [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide was added. Themixture was refluxed for 2.5 hr and the toluene solution decanted. Theresidue was partitioned between dilute sodium hydroxide and chloroform.The chloroform was dried and concentrated. The residue waschromatographed on a high pressure liquid chromatograph (Waters 500)using a silica column and eluting with ethyl acetate. The fractioncontaining material of molecular weight 257 was concentrated. Theresidue in isopropyl alcohol was treated with hydrogen chloride and theresulting crystals were collected. Yield of hydrochloride salt was 0.1 g(0.6%), m.p. 168°-171° C.

Analysis: Calculated for C₁₁ H₁₄ N₂ OSCl₂ : C, 45.06; H, 4.81; N, 9.55.Found: C, 45.15; H, 4.98; N, 9.26.

INTERMEDIATE 302,3,4,5-Tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,4]oxazepine-2-propanenitrile

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 100 g (0.415 mole) was partitioned between dilute aqueoussodium hydroxide (200 ml) and chloroform (200 ml). The organic layer wassaved and the aqueous layer extracted with chloroform (3×50 ml). Theorganic layer were combined, dried over sodium sulfate and concentratedby rotary evaporation (70° C., water aspirator). The residue, the freebase of the starting hydrochloride, 89 g (0.37 mole) was dissolved in150 ml of toluene and to the solution was added tetrabutyl ammoniumbromide, 9 g (0.027 mole). Saturated aqueous potassium cyanide (100 ml)was then added and the mixture stirred mechanically at reflux. After 2hr, additional tetrabutyl ammonium bromide, 3 g (0.009 mole) andsaturated aqueous potassium cyanide (20 ml) were added and the mixturestirred for 0.75 hr at reflux. The contents of the reaction vessel wereextracted with ethyl acetate (3×50 ml). (Note: chloroform should be usedinstead). The organic layer dried over sodium sulfate and concentratedby rotary evaporation (70° C., water aspirator) to 1/3 the originalvolume. Upon cooling, crystallization ensued. The crystals were filteredand washed with several portions of ethyl acetate and isopropyl ether.Thirty g (35%) of off-white crystals were collected, m.p. 104°-105° C. Asample was recrystallized from ethyl acetate, m.p. 104°-105° C.

Analysis: Calculated for C₁₂ H₁₃ N₃ O₂ : C, 62.33; H, 5.67; N, 18.17.Found: C, 62.06; H, 5.65 N, 17.97.

INTERMEDIATE 312-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride

To a stirred suspension of sodium hydride mineral oil (81.45 g of 60%dispersion 2.036 mole) in dimethylsulfoxide (500 ml) heated to 50° C.was added dropwise a solution of 2-chloronicotinic acid (142 g, 0.905mole) and N-ethyl-2-pyrrolidinol (99 g, 0.86 mole) in dimethylsulfoxide(500 ml) at a rate to maintain 55°-60° C. (occasional cooling wasnecessary). After the addition was complete, the mixture was stirred at50°-60° C. for 1.5 hr and allowed to cool. The solid which precipitatedwas filtered, washed with ethyl acetate and dried.

The dry sodium salt (172.53 g, 0.62 mole) was suspended in chloroform (1liter). Hydrogen chloride gas was bubbled through the suspension untilthe pH meter read 5.76. Triphenylphosphine (365.5 g, 1.395 mole) andCCl₄ (365.5 g) were added and the mixture stirred at reflux. After 45minutes, IR showed 95% reaction. Additional triphenylphosphine (100 g,0.38 mole) and CCl₄ (100 g) were added and the solution stirred atreflux an additional 45 min. IR showed>99% reaction. After cooling, thesolution was extracted several times with dilute hydrochloric acid (1.5liter total) The aqueous layer was then made basic with concentratedsodium hydroxide solution and extracted into chloroform (3×250 ml). Theorganic layer was dried over sodium sulfate and concentrated by rotaryevaporation (70° C., water aspirator). The residuel oil was dissolved inisopropyl alcohol (500 ml) and acidified with hydrogen chloride gas.Upon cooling, an oil was noted and the volume reduced to 1/3 theoriginal volume. Upon cooling, 70 g (0.241 mole, 28%) of pale browncrystals were collected, m.p. 153°-155° C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ Cl₂ : C, 49.50; H, 5.53; N, 9.62.Found: C, 49.64; H, 5.62; N, 9.32.

INTERMEDIATE 322-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-thionehydrochloride

2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride, approximately 50 g, waspartitioned between dilute aqueous sodium hydroxide (50 ml) andchloroform (50 ml). The organic layer was saved and the aqueous layerextracted with additional methylene chloride (2×50 ml). The organiclayers were combined, dried over sodium sulfate, filtered andconcentrated by rotary evaporation (70° C., water aspirator) yielding 39g (0.153 mole) of the free base. The free base thus obtained wasdissolved in chloroform (1.2 l), and phosphorus pentasulfide (33.9 g,0.153 mole) was added while stirring. The resulting mixture was heatedto reflux for 16 hr. After cooling, the reaction mixture was filtered,washed with dilute aqueous sodium hydroxide (3×300 ml), dried oversodium sulfate and concentrated by rotary evaporation (70° C., wateraspirator) to a yellow viscous oil. The oil was taken up in isopropylalcohol (˜200 ml) and made acidic with hydrogen chloride gas. Uponcooling, 20 g (43%) of crystals were collected, m.p. 133°-135° C.

Analysis: Calculated for C₁₂ H₁₈ N₂ OSCl₂ : C, 46.91; H, 5.25; N, 9.12.Found: C, 47.33; H, 5.38; N, 9.10.

INTERMEDIATE 337-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

A sample of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5-(4H)-onehydrochloride (10 g, 136 mole) was dissolved in dimethylformamide (150ml) and heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was thenadded dropwise over a period of 40-50 minutes. The reaction was allowedto stir at reflux for 30 minutes following the addition of SO₂ CL₂.After cooling, the contents of the flask were partitioned between water(150 ml) and benzene (150 ml). The benzene layer was saved and the waterlayer extracted with an additional amount of benzene (2×50 ml). Thebenzene extracts were combined and washed with dilute aqueous potassiumhydroxide (2×50 ml) followed by dilute aqueous hydrochloric acid (2×50ml). The benzene layer was dried over sodium sulfate and concentrated byrotary evaporation (˜70° C., water aspirator) yielding 2.61 g of crudematerial. The crude material was recrystallized from isopropyl ethergiving 1.25 g (12.6%) of off-white crystals, m.p. 78°-79° C.

Analysis: Calculated for C₁₁ H₁₂ N₂ O₂ Cl₂ : C, 48.02; H, 4.40; N,10.18. Found: C, 48.07; H, 4.53; N, 10.10.

INTERMEDIATE 347-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)thione

7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one, 6.0 g (0.022 mole) was suspended in 200ml of toluene. To this suspension was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-dilsulfide.The mixture was heated to reflux with vigorous stirring for 2 hours.Because the reaction was not complete, an additional amount (3.0 g) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide wasadded and the mixture stirred at reflux for 2 hr and left standing for56 hr at room temperature. The toluene layer was decanted and washedwith 50 ml of dilute aqueous sodium hydroxide and 50 ml of dilutehydrochloric acid. Toluene was removed by rotary evaporation (˜80° C.,water aspirator). The crude oil was recrystallized from isopropylalcohol giving 3.5 g (54%) of pale yellow crystals, m.p. 125°-127° C.

Analysis: Calculated for C₁₁ H₁₂ N₂ OSCl₂ : C, 45.37; H, 4.15; N, 9.62.Found: C, 45.40; H, 4.20; N, 9.71.

INTERMEDIATE 352-(Chloromethyl)-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one

A 15 g (0.05 mole) sample of sodium2-[(1-cyclohexyl-3-azetidinyl)oxy]-3-pyridine carboxylate obtained inPreparation 23 was suspended in 100 ml of chloroform and hydrogenchloride passed in until a pH of 5.8 remained steady. To the stirredmixture was added 18 g of thionyl chloride. The resulting solution wasstirred at room temperature for 3 hr. An I.R. spectrum showed a peak at1770 cm¹ which is characteristic of acid chloride. Forty milliliters oftriethylamine was added dropwise while cooling to about 25° C. with anice bath. The chloroform solution was stirred an additional 0.5 hr andwas extracted with water, dried over sodium sulfate and concentrated.The residue was chromatographed on a 7×20 cm silica column using ethanolas the eluent. The desired material was the first to be removed from thecolumn. The ethanolic solution was concentrated and the residuecrystallized once from ethyl acetate-isopropyl ether and once fromisopropyl alcohol. Yield of title compound was 1 g (7%), m.p. 120°-122°C.

Analysis: Calculated for C₁₅ H₁₉ N₂ O₂ Cl: C, 61.12; H, 6.50; N, 9.50.Found: C, 61.11; H, 6.62; N, 9.32.

INTERMEDIATE 362-(2-Chloroethyl)-2,3-dihydro-4-(phenylmethyl)pyrido[3,2-f][1,4]oxazepin-5(4H)one

The title compound was prepared in crude form in the first part ofExample 67.

INTERMEDIATE 372,3-Dihydro-2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

To a solution of 4.92 g (0.02 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)onein 35 ml of dimethylformamide was added 7.55 g (0.041 mole) of potassiumphthalimide. The mixture was stirred for 5 hr at 100° C. and leftstanding at room temperature overnight. Dimethylformamide was removed byrotary evaporation (80° C. vacuum pump). The residue was taken up in 100ml of chloroform and washed with water (2×30 ml) and 2M potassiumhydroxide (2×3 ml). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated by rotary evaporation (70° C., wateraspirator). The 6.26 g of crude product was recrystallized fromisopropyl alcohol to give 2.60 g (36%) white crystalline powder, m.p.146°-47° C.

Analysis: Calculated for C₁₉ H₁₇ N₃ O₄ : C, 64.95; H, 4.88; N, 11.95.Found: C, 65.18; H, 4.91; N, 12.09.

INTERMEDIATE 382-[2-(2,3-Dihydro-4-methyl-5(4H)-thioxopyrido[3,2-f][1,4-oxazepin-2-yl)-ethyl]-1H-isoindole-1,3(2H)-dione

To a solution of 1.0 g (0.0038 mole) of 2-(2-chloroethyl)-2,3-dihydro-4methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione in 20 mldimethylformamide was added 1.43 g (0.0078 mole) of potassiumphthalimide. The mixture was heated to 100° C. for 6 hr with stirring.

The dimethylformamide was removed by rotary evaporation (70°, vacuumpump) and the residue taken up in chloroform (100 ml). The organic layerwas washed with 2N potassium hydroxide (2×30 ml), dried over anhydroussodium sulfate, filtered, and concentrated by rotary evaporation (˜70°C., water aspirator). The crude oil (1.2 g) was recrystallized fromisopropyl alcohol giving 0.95 g (68%) of pale white crystals, m.p.172°-73° C.

Analysis: Calculated for C₁₉ H₁₇ N₃ O₃ S: C, 62.11; H, 4.66; N, 11.44.Found: C, 61.86; H, 4.70; N, 11.53.

INTERMEDIATE 392,3,4,5-Tetrahydro-4-methyl-5-thioxopyrido[3,2-f][1,4]oxazepin-2-propanenitrile

To a solution of 11.0 g (0.04 mole) of2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,4]-oxazepine-2-propanenitrilein 175 ml toluene was added 10.5 g (0.026 mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. Thereaction mixture was heated to reflux for 2 hr with vigorous mechanicalstirring. Another 3.0 g (0.007 mole) of 2,4bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide wasadded and heating continued for 1 hr additional. The reaction mixturewas allowed to cool and stand overnight at room temperature. Toluene wasremoved by rotary evaporation (90° C., water aspirator) and the residuetaken up in 200 ml chloroform. This was washed with 2×50 ml 2M aqueouspotassium hydroxide and concentrated by rotary evaporator (90° C., wateraspirator). Crystallization ensued upon cooling. Recrystallization fromisopropyl alcohol afforded 1.60 g (13.8%) product, m.p. 155°-56° C.

Analysis: Calculated for C₁₂ H₁₉ N₃ OS: C, 58.28; H, 5.30; N, 16.99.Found: C, 58.00; H, 5.26; N, 17.13.

INTERMEDIATE 402-(2-Chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride

To a suspension of 59.6 g (60%) in oil, 1.49 mole) of sodium hydride in400 ml of tetrahydrofuran heated to reflux was added a solution of 110 g(0.71 mole) of 2-chloronicotinic acid and 81.3 g (0.71 mole) of1,4-dimethyl-3-pyrrolidinol in 400 ml of tetrahydrofuran at a rate suchthat good reflux was maintained (20-35 minutes). Heating at reflux wascontinued for 2 hr subsequent to the completion of the addition. Becausemass spectra showed 30% starting material at this point, 25.0 g (0.63mole) additional sodium hydride was added and reflux continued for 4 hr.The reaction mixture was left standing overnight.

The mixture was quenched with isopropyl alcohol and filtrationattempted. However, when filtration failed, the solvent was stripped offby rotary evaporation.

This crude salt was suspended in 1 liter of chloroform and hydrogenchloride gas was bubbled in until a pH of 6 was reached. To thissuspension was added 372 g (1.42 mole) of triphenylphosphine and 372 gcarbon tetrachloride and the entire mixture heated at reflux for 1.5 hr.However, reaction was not complete as evidenced by I.R. An additional100 g (0.38 mole) of triphenyl phosphine and 100 g of carbontetrachloride was added and reflux continued overnight. After coolingthe reaction, 100 g of triethylamine was added.

The reaction mixture was extracted with 4×200 ml of dil aqueoushydrochloric acid. The hydrochloric acid extracts were made basic withconc. sodium hydroxide and extracted into a total of 1 liter ofchloroform. The chloroform was removed by rotary evaporation (70° C.; 3mm) and the residue taken up in 300 ml toluene.

The toluene was extracted with 4×125 ml of dil aqueous hydrochloricacid. The hydrochloric acid extracts were combined and washed with 4×200ml of methylene chloride. The hydrochloric acid layer was basified withconc. sodium hydroxide and extracted with methylene chloride. Theorganic extracts were combined, dried over sodium sulfate, filtered andconcentrated by rotary evaporation. The residue was taken up inisopropyl alcohol and treated with hydrogen chloride gas. Approximately34 g (16%) of white crystals were collected. Recrystallization inisopropyl alcohol gave an analytical sample, m.p. 178°-81° C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ Cl₂ : C, 49.50; H, 5.54; N, 9.62.Found: C, 49.46; H, 5.54; N, 9.50.

INTERMEDIATE 412-(2-Chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onehydrochloride

To a suspension of 60 g (60% in oil, 1.5 mole) of sodium hydride in 400ml of tetrahydrofuran heated to reflux was added a solution of 110 g(0.70 mole) of 2-chloronicotinic acid and 80 (0.70 mole) of1,3-dimethyl-3-pyrrolidinol so as to maintain good reflux. Heating atreflux was continued overnight. The mass spectra showed very littleproduct at this point; therefore, 400 ml of dimethylformamide was addedand heating at 77° C. was continued overnight. Approximately 10% of thedesired product was then observed by mass spectra. The tetrahydrofuranwas evaporated by passing nitrogen gas over the reaction mixture whileat the same time being replaced with dimethylformamide. The temperaturewas concomitantly increased to 100° C. The mixture was stirred overnightat 100° C. After cooling, no salt precipitated out; therefore,dimethylformamide was removed by rotary evaporation (90° C.; 5 mm).Approximately 250 g of crude salt was collected.

Into a suspension of 230 g (18 0.88 mole) of this crude salt in 1 literof chloroform was bubbled hydrogen chloride gas to pH 6. To thissuspension was added 463 g (1.77 mole) of triphenyl phosphine and 463 gof carbon tetrachloride. The mixture was then heated to reflux. After 8minutes a vigorous exotherm ensued which subsided in 30 minutes. Refluxwas continued for 2.5 hr. According to infrared analysis, the reactionwas near completion. Approximately 40 ml of triethylamine was added todrive the reaction to completion. The mixture was left standingovernight at room temperature.

The reaction mixture was extracted with 700 ml dil. ag. hydrochloricacid. The hydrochloric acid extracts were combined and washed with 4×100ml of chloroform. The combined aqueous hydrochloric acid extracts werethen made basic with conc. sodium hydroxide and extracted with 5×200 mlof methylene chloride. The organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated by rotaryevaporation (70° C.; 30 mm). The residue was taken up in 600 ml oftoluene and treated with activated charcoal 4 times. The toluene wasthen removed by rotary evaporation and the residue treated with hydrogenchloride in isopropyl alcohol which afforded 53 g (21%).Recrystallization from isopropyl alcohol afforded an analytically puresample, m.p. 155°-158° C.).

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ Cl₂ : C, 49.50; H, 5.54; N, 9.62.Found: C, 49.49; H, 5.61; N, 9.75.

INTERMEDIATE 422-(2-Chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]1,4-oxazepine-5(4H)-thione

To a suspension of 4.6 g (0.04 mole) of phosphorus pentasulfide in 50 mlof acetonitrile was added, all at once, a solution of 20 g (0.079 mole)of2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 50 ml of acetonitrile. The mixture was heated to reflux for 4 hr withstirring, at which time the mass spectra showed no starting material.The reaction was left standing overnight at room temperature.

To the reaction mixture was added 100 ml of toluene followed by stirringfor 15 minutes. Some tar-like material collected on the sides of thereaction vessel. The solution was filtered with much difficulty. Thefiltrate was saved and washed cautiously with 3×50 ml of saturatedaqueous sodium bicarbonate. The organic phase was dried over anhydroussodium sulfate, treated with activated charcoal, filtered, dried againover anhydrous sodium sulfate, filtered, and concentrated by rotaryevaporation (80° C.; 30 mm). The crude oil (9.2 g) was crystallized fromisopropyl alcohol, giving 6.0 g (28%) of yellow crystals, m.p. 119°-121°C.

Analysis: Calculated for C₁₂ H₁₅ N₂ OSCl: C, 53.23; H, 5.58; N. 10.35.Found: C, 53.05; H, 5.60; N, 10.34.

INTERMEDIATE 432-(2-Chloropropyl)-2,3-dihydro-4-methylpyrido[3,2-f]1,4-oxazepin-5(4H)-onehydrochloride

To a suspension of 36.1 g of 60% sodium hydride in oil (0.90 mole) in300 ml of tetrahydrofuran heated to reflux and under a nitrogen blanketwas added a solution of 68.3 g (0.43 mole) of 2-chloronicotinic acid and50 g (0.43 mole) of 1,2-dimethyl-4-pyrrolidinol in 300 ml oftetrahydrofuran at a rate such that good reflux was maintained (20 min).Subsequent to this addition, heating at reflux was maintained for 2.5 hrat which time the reaction appeared to be complete (by mass spec.). Thecrude sodium salt was filtered and washed with ethyl acetate affording135 g of the crude sodium salt.

To a suspension of 115 g (˜0.44 mole) of the above sodium salt in 650 mlof chloroform was added hydrogen chloride to reach a pH of 6. To thismixture was added 231.8 g (0.88 mole) of triphenylphosphine and 231.8 gof carbon tetrachloride and the entire reaction mixture heated to refluxfor 3 hr. After cooling, the reaction mixture was extracted with 4×250ml of di hydrochloric acid. The aqueous layer was washed with 4×125 mlof chloroform and made basic with concentrated sodium hydroxide. Theaqueous layer was then extracted with 3×250 ml of chloroform. Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated by rotary evaporation. To the residue wasadded 800 ml of toluene and the resulting solution decolorized 3 timeswith activated charcoal. The solvent was removed by rotary evaporation(90° C., 30 mm). The residue was taken up in 300 ml of isopropyl alcoholand the solution was saturated with hydrogen chloride, seeded, and leftstanding overnight at room temperature. Approximately 30 g (˜23%) ofsalt was collected. An analytical sample was prepared byrecrystallizating the salt 3 times from isopropyl alcohol, m.p. 143°-49°C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ Cl₂ : C, 49.50; H, 5.54 N, 9.62.Found: C, 49.85; H, 5.62 N, 9.84.

INTERMEDIATE 442-(2-Chloropropyl)-2,3-dihydro-3-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione

To a suspension of 4.90 g (0.022 mole) of phosphorus pentasulfide in 30ml of acetonitrile was added a solution of 10 g (0.039 mole) of2-(2-chloropropyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 25 ml of acetonitrile. The mixture was heated to reflux, withstirring, for 5.5 hours and left standing at room temperature overnight.To the reaction mixture was added 50 ml of toluene, followed by stirringfor a few minutes. The mixture was filtered and the residue washed with25 ml of toluene/acetonitrile. The filtrate was washed cautiously with3×75 ml of saturated aqueous sodium bicarbonate, dried over anhydroussodium sulfate, filtered, treated with activated charcoal, filtered andconcentrated by rotary evaporation (90° C.; 30 mm). The crude syrup(10.0 g) was crystallized from isopropyl ether/isopropyl alcohol, giving5 g of yellow crystals, m.p. 95°-97° C. A second crop was collected,bringing the total to 6 g (57%).

Analysis: Calculated for C₁₂ H₁₅ N₂ OSCl: C, 53.28; H, 5.58; N, 10.35.Found: C, 53.13; H, 5.58; N, 10.35.

INTERMEDIATE 452-(2-Chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionehydrochloride

To a suspension of 5.35 g (0.024 mole) of phosphorus pentasulfide in 25ml of acetonitrile was added a solution of 10.9 g (0.043 mole) of2-(2-chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 25 ml of acetonitrile. The mixture was heated to reflux for 2.75 hrand left standing at room temperature overnight.

To the cooled reaction mixture was added 50 ml of toluene, followed byfiltration. The residue was washed with 45 ml of 3/1, V/Vtoluene/acetonitrile. The filtrate was washed cautiously with 3×75 ml ofsaturated sodium bicarbonate, dried over anhydrous sodium sulfate,filtered, treated with activated charcoal, filtered, and concentrated byrotary evaporation. The residue was treated with hydrogen chloride inisopropyl alcohol/isopropyl ether which yielded one crop of 4.5 g ofyellow crystals, m.p. 148°-51° C. [(Note: a second crop of 1.5 g wascollected, bringing the total yield to 6.0 g (45.4%)].

Analysis: Calculated for C₁₂ H₁₆ N₂ OSCl₂ : C, 46.91; H, 5.25; N, 9.12.Found: C, 48.86; H, 5.34; N, 9.06.

INTERMEDIATE 462-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quiolin-5(4H)-one

To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml of tetrahydrofuranat -70° C. was added dropwise, at a rate to keep the temperature between-70° and -60° C., 61.1 ml of 2.7M n-butyllithium (0.16 mole). Thetemperature was maintained at -70° C.±3° C. for 20 minutes. A solutionof 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise at arate such that temperature remained between -70° and -60° C. After 20minutes, the darkened reaction solution was poured onto a large excessof dry ice. The solvent was evaporated with a stream of air.

The residue was taken up in 300 ml of water, made basic with diluteaqueous sodium hydroxide and washed with 3×50 ml of isopropyl ether. Theaqueous phase was filtered and treated with dilute hydrochloric acid to˜pH 4-5, at which time a copious precipitate formed. The precipitate wascollected and the filtrate reacidified yielding more precipitate. Theprecipitates were combined and washed with water, isopropyl alcohol, andisopropyl ether. Approximately 15.4 g (61.5%) of off-white crystals werecollected.

To a suspension of 4.0 of 60% sodium hydride in oil (0.10 mole) in 100ml tetrahydrofuran heated to reflux was added a solution of 5.5 g (0.048mole) of N-methyl-3-pyrrolidinol and 10 g (0.048 mole) of the aboveprepared 2-chloro-3-quinolinecarboxylic and in 50 ml of tetrahydrofuranat such rate as to maintain good reflux. Reflux was maintained for 1.5hr and the reaction mixture cooled. The solvent was removed by rotaryevaporation yielding 26 g crude product.

The entire crude product from above was suspended in 150 ml chloroformand hydrogen chloride bubbled in until pH of 5.76 was reached (note:after hydrogen chloride addition ceased, the pH continued to lower to1.7). To this suspension was added 25.0 g (0.096 mole) oftriphenylphosphine and 25 g of carbon tetrachloride. After 45 min, anadditional 10 g (0.038 mole) of triphenylphosphine and 10 g of carbontetrachloride was added. After 30 minutes, the heat was removed and thereaction driven to completion by dropwise addition of 20 ml oftriethylamine.

The reaction mixture was extracted with 3×50 ml of 3N hydrochloric acid.The aqueous extracts were combined, washed with 2×50 ml chloroform, madebasic with concentrated sodium hydroxide and extracted with 3×50 ml ofchloroform. The organic extracts were combined and concentrated byrotary evaporation. The syrupy residue was taken up in 100 ml of tolueneand treated with activated charcoal. The toluene was removed by rotaryevaporation and the syrupy residue crystallized from isopropyl alcohol,giving 1.5 g (11%) of white crystals, m.p. 133°-134° C.

Analysis: Calculated for C₁₅ H₁₅ N₂ O₂ Cl: C, 61.97; H, 5.20; N, 9.63.Found: C, 61.73; H, 5.18 N, 9.54.

INTERMEDIATE 472-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]quinoline-5(4H)-thione

To 3.0 g (0.01 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-onein 30 ml of acetonitrile was added 1.3 g (0.006 mole) of phosphoruspentasulfide. The mixture was stirred vigorously at reflux for 2 hr.After cooling, the reaction mixture was diluted with 60 ml of tolueneand filtered. The residue on the filter paper was washed with 50 ml ofadditional toluene/acetonitrile, 3/1, V/V. The filtrate was washed with3×50 ml saturated sodium carbonate (caution: gas evolved), dried overanhydrous sodium sulfate, filtered, treated with activated charcoal,filtered again and concentrated by rotary evaporation (90° C., 30 mm).The residual syrup was crystallized from isopropyl alcohol, yielding 1.6g (52%) of yellow crystals, m.p. 114°-116° C.

Analysis: Calculated for C₁₅ H₁₅ N₂ OClS: C, 58.72; H, 4.93; N, 9.13.Found: C, 38.38; H, 4.92; N, 9.07.

INTERMEDIATE 482-(2-Chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino[6,7-c]quininolin-5(4H)-onehydrochloride

To a suspension of 3.16 g (60% in oil, 0.08 mole) of sodium hydride in250 ml of tetrahydrofuran under dry nitrogen atmosphere heated to refluxwas added a solution of 10.42 g (0.038 mole) of4-chloro-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 3.81 g(0.038 mole) of N-methyl-3-pyrrolidinol in 50 ml of tetrahydrofuran atsuch a rate as to maintain good reflux. Heating at reflux was continuedfor 3 hr. The solvent was removed by rotary evaporation (80° C., 30 mm),and the crude sodium salt (12 g) was dried overnight.

The entire amount of crude sodium salt was suspended in 250 ml ofmethylene chloride. Hydrogen chloride was added to a pH of 2. To thissuspension was added 19.4 g (0.074 mole) of triphenyl phosphine and 19.4g of carbon tetrachloride. The extire mixture was heated to reflux for 3hrs. IR indicated presence of acid chloride; therefore, the reaction wasdriven to completion by the addition of 15 ml of triethylamine. Aftercooling, the reaction mixture was extracted with 2×75 ml of 3Nhydrochloric acid. The acid washings were combined and washed with 75 mlof methylene chloride. The water layer was made basic (after coolingwith ice) and extracted with 3×75 ml methylene chloride. The methylenechloride was removed by rotary evaporation and the residue taken up in100 ml of toluene. The solution was treated with activated charcoal,filtered, and concentrated by rotary evaporation (90° C., 30 mm). Theresidue was dissolved in isopropyl alcohol and acidified with etherealhydrogen chloride. Approximately 1.1 g (7.3%) of white needles werecollected, m.p. 172°-174° C.

Analysis: Calculated for C₁₆ H₁₅ N₂ O₂ Cl₂ F₃ : C, 48.63; H, 3.83; N,7.09. Found: C, 48.78; H, 3.84; N, 7.04.

INTERMEDIATE 492-(2-Chlorophenyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl-1,4-oxazepino[6,7-c]quinoline-5(4H)-thione

To a suspension of 0.85 g (0.004 mole) of phosphorus pentasulfide in 25ml of acetonitrile was added to a solution of 2.3 g (0.0064 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino[6,7-c]quinolin-5(4H)-oneand the mixture heated to reflux. TLC in ethyl acetate showed only 50%conversion; therefore, 0.5 g (0.0022 mole) of phosphoruspentasulfide wasadded. After an additional 2 hr, no change was seen in startingmaterial/product. Heat was removed and the reaction mixture leftstanding overnight. The mixture was diluted with 75 ml of toluene andwashed cautiously (gas evolved) with 3×50 ml of saturated sodiumbicarbonate. The solvent was removed by rotary evaporation and theresidue combined with a previous run of the same material. The combinedproducts were purified by column chromatography over silica gel elutingwith ethyl acetate. The solvent was removed from the fractionscontaining the product giving 0.9 g of yellow oil. The oil wasrecrystallized from isopropyl ether giving 0.55 g of yellow crystals,m.p. 135°-37° C.

Analysis: Calculated for C₁₆ H₁₄ N₂ OSF₃ Cl: C, 51.27; H, 3.77; N, 7.47.Found: C, 51.41; H, 3.83; N, 7.42.

INTERMEDIATE 502-Chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H)1,4-benzodiazepin-5-one

To a stirring solution of 266 ml (0.64 mole) of 2.4 m butyllithiumsolution in hexane, was slowly added 117.5 g (0.58 mole) ofN-methyl-N-phenyl-1-(1-methylethyl)-3-azetidineamine. The temperature ofthe mixture rose to 55° C. which was then allowed to reflux for 5.5hours. When cooled, the solution was poured slowly with vigorousstirring onto a slurry of dry ice in hexane and allowed to standovernight. The residue was dissolved in chloroform and 117.0 g (1.16mole) of phosphorous oxychloride was added dropwise while stirring. Thesolution was refluxed for two hours. Upon cooling, the solution waswashed, first with a dilute hydrochloric acid solution, then with adilute sodium hydroxide solution. The hexane layer was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was dissolved in hot isopropyl ether. The crystals obtained oncooling were recrystallized from the same solvent. The white solidweighed 45.0 g (29%). The solid was recrystallized twice more to give ananalytical sample, m.p. 90°-92° C.

Analysis: Calculated for C₁₄ H₁₉ Cl₁ N₂ O: C, 63.03; H, 7.18; N, 10.50.Found: C, 62.59; H, 7.09; N, 10.40.

INTERMEDIATE 512-(2-Chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one

To 206 g (1 mole) of 1-ethyl-3-methylanilinopyrrolidine was added 660 ml(1.05 moles) of 14.98% butyllithium in hexane and the solution refluxedfor 2 hours and poured on solid carbon dioxide. The carbon dioxidehexane mixture was allowed to evaporate overnight, leaving a dry yellowsolid. The solid was dissolved in chloroform. To this solution was addeddropwise with stirring 1 mole of phosphorous trichloride. Thetemperature rose to reflux during addition and remained there throughoutmost of the addition. When the addition was complete, the mixture wasstirred one hour and water was added cautiously. The resulting mixturewas made basic with sodium hydroxide. The chloroform layer wasseparated, dried over anhydrous sodium sulfate and concentrated. Theresidue was crystallized from isopropyl ether to yield 112 g (42%), m.p.75°-79° C. A 25 g sample was recrystallized from isopropyl ether to give18 g of product, m.p. 78°-80° C.

Analysis: Calculated for C₁₄ H₁₉ N₂ O₁ Cl: C, 63.03; H, 7.18; N, 10.50.Found: C, 63.27; H, 7.22; N, 10.55.

INTERMEDIATE 526-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H-one

To a suspension of 2.1 g (60% in oil, 0.052 mole) of sodium hydride in125 ml of dimethylformamide heated to 60° C. under a nitrogen gasblanket was added a solution of 2.65 g (0.026 mole) ofN-methyl-3-pyrrolidinol and 5.0 g (0.026 mole) of3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethylformamidedropwise at such a rate as to maintain 60° C. Subsequent to thisaddition, the mixture was heated to 75° C. for 3 hr. The solvent wasthen removed by rotary evaporation (60° C., 5 mm). The entire solidresidue was suspended in 150 ml methylene chloride and hydrogen chlorideadded until a pH of 3 was reached. To the resulting mixture was added 15g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride andthe entire mixture heated to reflux. After 1 hr, 7.5 g (0.029 mole) oftriphenylphosphine and 7.5 g carbon tetrachloride were added, followedby the same increments 1 hr later. The reaction was driven to completionby adding 20 ml of triethylamine. The reaction mixture was washed with6×50 ml of 3N hydrochloric acid, dried over sodium sulfate, filtered andconcentrated by rotary evaporation. To the residue was added ethylacetate, which caused much tarry material to fall out of solution,leaving the desired product and triphenylphosphine oxide in solution.The mixture was chromatographed by column chromatography using silicagel as the stationary phase and ethyl acetate as eluent. Similarfractions were combined and ethyl acetate removed by rotary evaporation,yielding 0.6 g (7%), of white crystals, m.p. 134°-38° C.

Analysis: Calculated for C₁₁ H₁₂ N₂ O₂ Cl₂ : C, 48.02; H, 4.40 N, 10.18.Found: C, 47.89; H, 4.38; N, 10.12.

INTERMEDIATE 532-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinolin-5(4H)-one

Following the procedure of Intermediate 8,5-[(1-methyl-3-pyrrolidinyl)oxy]-6-isoquinolinecarboxamide is convertedto the title compound.

INTERMEDIATE 542-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7.6-f]isoquinoline-5(4H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinoline-5(4H)-oneis sulfurized to give the title compound.

INTERMEDIATE 552-(2-Chloroethy)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7g]isoquinolin-5(4H)-one

Following the procedure of Intermediate 8,7-[(1-methyl-3-pyrrolidinyl)oxy]-6-isoquinolinecarboxamide is convertedto the title compound.

INTERMEDIATE 562-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g]isoquinoline-5(4H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g]isoquinolin-5(4H)-oneis sulfurized to give the title compound.

INTERMEDIATE 572-(2-Chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-one

Following the procedure of Intermediate 8,5-methyl-8-[(1-methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide isconverted to the title compound.

INTERMEDIATE 582-(2-Chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-oneis sulfurized to give the title compound.

INTERMEDIATE 592-(2-Chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-one

Following the procedure of Intermediate 8,2-methyl-8[(1-methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide isconverted to the title compound.

INTERMEDIATE 602-(2-Chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxzaepino[6,7-h]quinoline(5-4H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-oneis sulfurized to give the title compound.

INTERMEDIATE 61 2-(2-Chloroethyl)-3,4-dihydro-2-methyl1,4]-oxazepino[6,7-f]quinolin-1(2H)-one

Following the procedure of Intermediate 8,6-[(1-methyl-3-pyrrolidinyl)-oxy]-5-quinolinecarboxamide is converted tothe title compound.

INTERMEDIATE 624-(2-Chloroethyl)-3,4-dihydro-2-methyl[1,4-oxazepino[6,7-f]quinoline-1(2H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-3,4-dihydro-2-methyl[1,4]-oxazepino[6,7-f]quinolin-1(2H)oneis sulfurized to give the title compound.

INTERMEDIATE 632-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-one

Following the procedure of Intermediate 8,8-[(1-methyl-3-pyrrolidinyl)oxy-]-7-quinolinecarboxamide is converted tothe title compound.

INTERMEDIATE 642-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thione

Following the procedure of Intermediate 47,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-oneis sulfurized to give the title compound.

INTERMEDIATE 65(S)-2-(2-Chloroethyl)2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride[1:1]

A solution of 47.4 g (0.3 mole) of 2-chloronicotinic acid and 30 g (0.3mole) of -(S)-1-methyl-3-pyrrolidinol in 400 ml of tetrahydrofuran wasadded over a period of 1 hr to a stirred suspension of 26.4 g (0.66mole) of 60% sodium hydride)mineral oil in 500 ml of tetrahydrofuran at50°-60° C. The mixture was stirred at reflux for 2.5 hr and allowed tocool to 25° C. About 400 ml of methylene chloride was added to theslurry followed by the dropwise addition of 34.5 g (0.36 mole) ofmethane sulfonic acid in 100 ml of methylene chloride. The mixture wasstirred 10 min and 157 g (0.6 mole) of triphenylphosphine was addedfollowed in 200 ml of carbon tetrachloride. The mixture was heated toreflux for 1 hr. To the cooled (25° C.) solution was added at a rapiddrop, 100 ml of triethylamine. The solution was concentrated on therotary evaporator and the residue was partitioned between methylenechloride and dilute hydrochloric acid. The methylene chloride wasextracted 6 times with dilute hydrochloric acid. The acid extracts werecombined, made basic with sodium hydroxide and extracted withchloroform. The extract was dried over sodium sulfate and concentrated.The residue was dissolved in isopropyl alcohol and treated with asolution of hydrogen chloride in isopropyl alcohol. The resultinghydrochloride salt weighed 21 g (25%). One gram of the salt wasrecrystallized from isopropyl alcohol, m.p. 149°-151° C. [α]_(D) ²⁵=-38.3 (water).

Analysis: Calculated for C₁₁ H₁₄ N₂ O₂ Cl₂ : C, 47.67; H, 5.09; N,10.11. Found: C, 47.66; H, 5.11; N, 10.11.

INTERMEDIATE 66(S)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

A 20 g sample of(S)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onehydrochloride[1:1] was partitioned between chloroform and dilute sodiumhydroxide. The chloroform was dried over soduum sulfate andconcentrated. The residue was crystallized from isopropyl ether. A yieldof 16 g was obtained, m.p. 61°-62° C. [α]_(D) ²⁵ =-22.95 (methanol).

Analysis: Calculated for C₁₁ H₁₃ N₂ O₂ Cl: C, 54.89; H, 5.44; N, 11.64.Found: C, 54.89; H, 5.47; N, 11.59.

INTERMEDIATE 67(R)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-onehydrochloride[1:1]

A solution of 47.4 g (0.3 mole) of 2-chloronicotinic acid and 30 g (0.3mole) of (R)-1-methyl-3-pyrrolidinol in 400 ml of tetrahydrofuran wasadded over a period of 1 hr to a stirred suspension of 26.4 g (0.66mole) of 60% sodium hydride/mineral oil in 500 ml of tetrahydrofuran at55°-60° C. The mixture was stirred at reflux for 2.5 hr and allowed tocool to 25° C. About 400 ml of methylene chloride was added to theslurry followed by a dropwise addition of 34.5 g (0.36 mole) of methanesulfonic acid in 100 ml of methylene chloride. The mixture was stirredfor 10 min and 157 g (0.6 mole) of triphenylphosphine was added followedby 200 ml of carbon tetrachloride. The mixture was heated to reflux for4 hr. To the cooled (25° C.) solution was added 100 ml of triethylamineat a rapid drop. The solution was concentrated on the rotary evaporatorand the residue was partitioned between methylene chloride and dilutehydrochloric acid. The methylene chloride was extracted 6 times withdilute hydrochloric acid. The acid extracts were combined, made basicwith sodium hydroxide and extracted with chloroform which was dried andconcentrated. The residue was dissolved in isopropyl alcohol and treatedwith a solution of hydrogen chloride in isopropyl alcohol. The resultinghydrochloride weighed 25 g (30%). One gram was recrystallized fromisopropyl alcohol, m.p. 152°-154° C.; [α]_(D) ²⁵ =+36.2 (water).

Analysis: Calculated for C₁₁ H₁₄ N₂ O₂ Cl₂ : C, 47.67; H, 5.09; N,10.11. Found: C, 47.65; H, 5.20; N, 9.03.

INTERMEDIATE 68(R)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

A 24 g sample of(R)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-onehydrochloride[1:1] was partitioned between chloroform and sodiumhydroxide solution. The chloroform extract was dried over sodium sulfateand concentrated. The residue was crystallized from isopropyl ether.Yield of title compound was 19 g, m.p. 61°-62° C.; [α]_(D) ²⁵ =(+) 22.4(methanol).

Analysis: Calculated for C₁₁ H₁₃ N₂ O₂ Cl: C, 54.89; H, 5.44; N, 11.64.Found: C, 54.93; H, 5.51; N, 11.67.

INTERMEDIATE 69(S)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione

To a stirred suspension of 7.8 g (0.0176 mole) of phosphoruspentasulfide in 65 ml of acetonitrile was added 15.6 g (0.065 mole) of(S)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-oneand the mixture was stirred at reflux for 3 hr. About 50 ml of toluenewas added and the mixture was cooled to 25° C. and the liquid wasdecanted. The liquid was washed with aqueous potassium bicarbonate,treated with magnesium sulfate and charcoal, and filtered. The filtratewas concentrated, leaving 4.5 g of solid. The pot residue was stirredwith a mixture of aqueous potassium bicarbonate, chloroform, andacetonitrile. The organic layer was collected, dried over magnesiumsulfate and concentrated. The solid residue (10.5 g) was combined withthe above solid, giving a total of 15 g which was recrystallized from amixture of isopropyl and ethyl alcohols. Yield of title compound was12.2 g (73%). A one gram sample was recrystallized from isopropylalcohol-chloroform, m.p. 168°-170° C.; [α]_(D) ²⁵ =(+) 48.2°(chloroform).

Analysis: Calculated for C₁₁ H₁₃ N₂ OSCl: C, 51.46; H, 5.10; N, 10.91.Found: C, 51.24; H, 5.10; N, 10.85.

INTERMEDIATE 70(R)-2-(2-Chloroethyl)-2,3-dihydro-4-methhlpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione

To a suspension of 9 g (0.02 mole) of phosphorus pentasulfide in 75 mlof acetonitrile was added 18 g (0.075 mole) of(R)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-oneand the mixture was stirred at reflux for 2.5 hr, cooled and treatedwith 60 ml of toluene. The mixture was filtered and the solid washedtwice with 30 ml of 25% acetonitrile-75% toluene. The volume was made toabout 400 ml with 50% toluene-50% acetonitrile and extracted withsaturated aqueous potassium bicarbonate. The organic layer wasseparated, treated with magnesium sulfate and charcoal, and filtered.The filtrate was concentrated and the residue was recrystallized fromisopropyl alcohol-chloroform. Yield of title compound was 13 g (68%),m.p. 168°-170° C.; [α]_(D) ²⁵ =(-) 47.4 (chloroform).

Analysis: Calculated for C₁₁ H₁₃ N₂ OSCl: C, 51.46; H, 5.10; N, 10.91.Found: C, 51.23; H, 5.12; N, 10.80.

INTERMEDIATE 717-Bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

To a suspension of 51.2 g of 60% sodium hydride in oil (1.28 mole) in 1liter of tetrahydrofuran heated to reflux, and under nitrogen atmospherewas added a solution of 144 g (0.61 mole) of5-bromo-2-chloropyridine-3-carboxylic acid and 61.6 g (0.61 mole) ofN-methyl-3-pyrrolidinol in 1 liter of tetrahydrofuran dropwise at reflux(˜1 hr). Heating was continued at reflux with vigorous agitation for 1.5hr. After cooling, approximately 5 ml of water was added and the mixturesoon solidified. Additional tetrahydrofuran was added to aid instirring. The mixture was filtered, washed with several portions oftetrahydrofuran, and dried at 50° C., 0.05 mm Hg, overnight to give 190g of crude sodium salt.

The entire amount of crude sodium salt (190 g) was added slowly to 1000g of thionyl chloride cooled in an ice bath. The reaction mixture wasstirred for 10 minutes at ˜10° C. and 10 minutes at room temperature.Excess thionyl chloride was removed by rotary evaporation at 65° C., 30mm Hg and the residue azetroped twice with toluene. The residue wastaken up in ˜1 liter of methylene chloride and diisopropylethyl amineand was added slowly until the solution just turned basic. The mixturewas stirred for 1 hr at room temperature and washed successively with2×200 ml of 1N hydrochloride acid, 2×200 ml of dilute sodium hydroxideand 100 ml of water. The organic phase was dried over sodium sulfate,filtered, and concentrated by rotary evaporation. The black residue wastriturated 5 times with 5% toluene in diisopropyl ether to give 60 g(31%) of light brown crystals. A sample was recrystallized fromdiisopropyl ether, m.p. 71°-75° C.

Analysis: Calculated for C₁₁ H₁₂ N₂ O₂ BrCl: C, 41.34; H, 3.79; N, 8.77.Found: C, 41.35; H, 3.81; N, 8.89.

INTERMEDIATE 727-Bromo-2-[2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione

To a solution of 5.9 g (0.016 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 25 ml of acetonitrile was added 2.07 g (0.005 mole) of phosphorouspentasulfide. The mixture was heated to reflux for 3 hr. The reactionmixture was diluted with 100 ml of toluene and filtered. The filtratewas washed with 3×50 ml of saturated sodium bicarbonate and 50 ml ofwater, dried over sodium sulfate, filtered, and concentrated by rotaryevaporation to ˜5-10 ml. Crystallization ensued and 3.0 g of crystalswere collected. The mother liquor was concentrated giving 1.0 gadditional crystals. The two crops were combined and recrystallized fromdiisopropylether/toluene to give ˜3 g (56%) of yellow crystals, m.p.138°-141° C.

Analysis: Calculated for C₁₁ H₁₂ N₂ OSBrCl: C, 39.36; H, 3.60; N, 8.35.Found: C, 39.54; H, 3.63; N, 8.43.

INTERMEDIATE 732-(2-Chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrate[1:1]

To a suspension of 22 g of sodium hydride (60% in oil, 0.55 mole) in 600ml of tetrahydrofuran at reflux and under nitrogen atmosphere was addeda solution of 85 g (0.5 mole) of 2-chloro-6-methyl-3-pyridinecarboxylicacid and 50 g (0.5 mole) of N-methyl-3-pyrrolidinol in 1 liter oftetrahydrofuran at a rate to maintain good reflux. Heating was continuedfor 6 hr and a suspension of 2.5 g (0.025 mole) ofN-methyl-3-pyrrolidinol and 1.0 g of sodium hydride (60% in oil, 0.025mole) in 25 mole of tetrahydrofuran was added. After heating for another45 minutes, 1 ml of water was added and the reaction allowed to standovernight at room temperature. The solvent was then removed by rotaryevaporation. Hexane was added to the viscous, semi-crystalline material.The precipitate was filtered to give 78 g of material. The mother liquorwas concentrated by rotary evaporation and allowed to stand at roomtemperature for 2 days to give another 50 g of material.

To a suspension of 130 g of the above material in 1200 ml of chloroformwas added hydrogen chloride gas to pH 6 followed by 262 g (1.0 mole) oftriphenylphosphine and 262 g of carbon tetrachloride. The mixture washeated to reflux for 2.5 hr and an additional 80 g (0.3 mole) oftriphenylphosphine and 80 g of carbon tetrachloride was added. After 30min at reflux, the reaction flask was cooled in a water bath and ˜40 mlof diisopropylethylamine was added. The entire reaction mixture wasextracted with 3×500 ml of 1N hydrochloric acid. The acid extracts werecombined and washed with 3×300 ml of chloroform. The aqueous layer wasmade basic with concentrated sodium hydroxide and extracted with 3×400ml of methylene chloride. The organic layer was dried over sodiumsulfate, filtered, concentrated by rotary evaporation, treated twicewith activated charcoal in toluene and concentrated by rotaryevaporation. The residue was taken up in 600 ml of chloroform andextracted into 1N hydrochloric acid. The aqueous layer was made basicwith concentrated sodium hydroxide and extracted with 3×300 ml ofchloroform. The organic organic extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation. The residue wascrystallized from isopropyl ether and water to give 40 g (29%) of titlecompound, m.p. 73°-74° C.

Analysis: Calculated for C₁₂ H₁₇ N₂ O₃ Cl: C, 52.85; H, 6.28; N, 10.27.Found: C, 52.58; H, 6.02; N, 10.26.

INTERMEDIATE 742-(2-Chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionehydrate[1:1]

To a suspension of 17.4 g (0.043 mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-disulfide in˜300 ml of toluene was added 20 g (0.078 mole) of2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4-oxazepin-5(4H)-onehydrate[1:1]. The mixture was heated to reflux for 3 hr and 4.0 g (0.01mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide wasadded and heating was continued for 1 hr. After cooling, toluene wasdecanted off and washed with 3×100 ml 1N sodium hydroxide and 100 mlwater. The organic layer was then extracted with 2×100 ml of 2Nhydrochloric acid. The aqueous layer was made just basic to litmus withconc. sodium hydroxide causing the product to precipitate out. Of the 25g of crude collected, 2 g were recrystallized from diisopropyl ether togive pale yellow crystals, m.p. 80° -86° C.

Analysis: Calculated for C₁₂ H₁₇ N₂ O₂ ClS: C, 49.91; H, 5.93; N, 9.70.Found: C, 49.76; H, 5.72; N, 9.60.

INTERMEDIATE 752-(2-Chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-one

To a suspension of 109 g (60% in oil, 2.73 mole) of sodium hydride in800 ml of tetrahydrofuran under nitrogen atmosphere and at reflux wasadded a solution of 250 g (1.24 mole) of 2-chloro-5-nitro benzoic acidand 125 g (1.24 mole) of N-methyl-3-pyrrolidine in 1 liter oftetrahydrofuran at such a rate as to maintain good relux. The reactionmixture was heated at reflux for 3 hr. After cooling, concentratedhydrochloric acid was added until the reaction mixture was netural.Approximately 500 ml of isopropyl alcohol was added and the reactionmixture was filtered to remove sodium chloride. The filtrate wasconcentrated by rotary evaporation to give approximately 350 g ofresidue. To 30 g (0.11 mole) of this residue was added 100 ml of thionylchloride. After 10 min of stirring at room temperature, the thionylchloride was removed by rotary evaporation at 70° C., 30 mm Hg. Another30 ml of thionyl chloride was added and the thionyl chloride was againremoved by rotary evaporation. The residue was azeotroped once withtoluene and taken up in 200 ml of methylene chloride. To the reactionmixture was added diisopropyl ethyl amine until the mixture was justbasic. The reaction mixture was washed with 3×100 ml of 1N hydrochloricacid, 100 ml of water, and 3×200 ml of 1N sodium hydroxide, dried oversodium sulfate, filtered, concentrated by rotary evaporation,decolorized twice with activated charcoal in toluene, and concentratedagain by rotary evaporation. The crude residue yielded 5 g (16% based onstarting 2-chloro-5-nitrobenzoic acid) of light yellow crystals fromisopropyl ether/ethyl/acetate, mp. 91°-92° C.

Analysis: Calculated for C₁₂ H₁₃ N₂ O₄ Cl: C, 50.03; H, 4.60; N, 9.84.Found: C, 50.51; H, 4.57; N, 9.75.

INTERMEDIATE 762-(2-Chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione

To 2.0 g (0.007 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-onein 35 ml of acetonitrile was added 1.0 g (0.0023 mole) of phosphoruspentasulfide and the mixture heated to reflux for 2 hr. Another 0.4 g(0.001 mole) of phosphorus pentasulfide was added and heating continuedfor 2 hr. After cooling, the reaction mixture was diluted with 100 ml oftoluene and filtered. The filtrate was washed with 3×50 ml of saturatedsodium bicarbonate and 100 ml of water, dried over sodium sulfate,filtered, charcoaled, filtered, and concentrated by rotary evaporation.The crude oil was crystallized from isopropyl ether/toluene to give 1.2g (57%) of yellow crystals, m.p. 153°-155° C.

Analysis: Calculated for C₁₂ H₁₃ N₂ O₃ SCl: C, 47.92; H, 4.36; N, 9.31.Found: C, 48.03; H, 4.39; N, 9.15.

INTERMEDIATE 772-(2-Chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-one

Into a suspension of 22.7 g (0.095 mole) of5-fluoro-2-(1-methyl-3-pyrrolidinyloxy)benzamide in 350 ml of aceticacid cooled to 10° C. in an ice bath was bubbled hydrogen chloride for10 minutes. To this mixture was added 76.8 g (0.76 mole) ofn-butylnitrite through a dropping funnel equipped to deliver the liquidbelow the surface of the reaction mixture at 10°-15° C. The reactionmixture was stirred for 1 hr at 10°-15° C. and 18 hr at roomtemperature. The reaction mixture was heated to reflux for 2 hr. Thesolvent (acetic acid) was removed at 70° C., 0.5 mm Hg for 5 hrs byrotary evaporation affording 23 g of crude material. The crude materialwas further purified by dissolving in 1N hydrochloric acid, washing theaqueous with methylene chloride and removing the water.

To 5 g (0.021 mole) of this crude material was added 20 ml of thionylchloride and the reaction stirred at room temperature for 10 minutes.The thionyl chloride was removed by rotary evaporation (70° C., 30 mm)and the residue azeotroped once with toluene. The residue was taken upin 50 ml of methylene chloride and made basic by the careful addition ofdiisopropyl ethyl amine. The reaction mixture was washed with 2×50 ml of1H hydrochloric acid and 2×50 ml of 1N sodium hydroxide, dried oversodium sulfate and concentrated by rotary evaporation. The residue wastriturated with hot diisopropyl ether to give 1.1 g (18.5%) ofanalytically pure crystals, m.p. 113°-116° C.

Analysis: Calculated for C₁₂ H₁₃ NO₂ ClF: C, 55.93; H, 5.09; N, 5.44.Found: C, 55.91; H, 5.09; N, 5.52.

INTERMEDIATE 782-(2-Chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepine-5(4H)-thione

To 1.0 g (0.0039 mole) of2-(2-chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-onein 30 ml of acetonitrile was added 0.7 g (0.0016 mole) of phosphoruspentasulfide and the reaction mixture heated to reflux. After 2 hr,another 0.4 g (0.009 mole) of phosphorus pentasulfide was added andheating continued for 2 hr. The reaction mixture was diluted with 70 mlof toluene and filtered. The filtrate was washed carefully with 3×50 mlof saturated sodium bicarbonate and 50 ml of water, dried over sodiumsulfate, filtered, charcoaled, filtered and concentrated by rotaryevaporation. The crude material was recrystallized from diisopropylether to give 0.55 g (52%) of yellow crystals, m.p. 135°-137° C.

Analysis: Calculated for C₁₂ H₁₃ NOSClF: C, 52.65; H, 4.79; N, 5.12.Found: C, 52.60; H, 4.81; N, 5.08.

                                      TABLE 1                                     __________________________________________________________________________     ##STR26##                                                                     No.mediateInter-                                                                   A(Y).sub.0-2  B                                                                               R            R.sup.4                                                                           E   X                                                                                  ##STR27##                                                                             Salt                                                                             Isomer.sup.(a)O                                                              ptical              __________________________________________________________________________    1    benz          O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- Rac.                2    benz          O CH.sub.2C.sub.6 H.sub.5                                                                    H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   3    naphth[2,3-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   4    pyrido[3,2-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   5    8-Clbenz      O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   6    7-Brbenz      O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   7    7-Clbenz      O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   8    naphth[2,1-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   9    7-OCH.sub.3benz                                                                             O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   10   benz          S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   11   pyrido[3,2-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   12   naphth[2,3-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   13   8-Clbenz      S CH.sub. 3    H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   14   7-Brbenz      S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   15   naphth[2,1-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   16   pyrido[4,3-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   17   pyrido[3,4-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   18   pyrido[2,3-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   19   7-Clbenz      S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   20   7,9-diiodo-benz                                                                             O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   21   pyrido[3,2-f] S CH.sub.3     H   O   Cl   CH.sub. 2                                                                             HCl                                                                              "                   22   pyrido[4,3-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   23   7-OCH.sub.3benz                                                                             S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   24                                                                              (a)                                                                              benz          O C.sub.6 H.sub.11                                                                           H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (b)                                                                              benz          O C.sub.2 H.sub.5                                                                            H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (c)                                                                              benz          O CH(CH.sub.3).sub.2                                                                         H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (d)                                                                              benz          O 4-ClC.sub.6 H.sub.4CH.sub.2                                                                H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (e)                                                                              benz          O 4-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (f)                                                                              benz          O 3,5-(OCH.sub.3).sub.2                                                                      H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                                        C.sub.6 HCH.sub.2                                          (g)                                                                              benz          O 3-CF.sub.3C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                     (h)                                                                              benz          O 4-NO.sub.2C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   25                                                                              (a)                                                                              pyrido[3,2-f] O C.sub.6 H.sub.11                                                                           H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                     (b)                                                                              pyrido[3,2-f] O C.sub.2 H.sub.5                                                                            H   O   Cl   (CH.sub.2).sub.2                                                                      HCL                                                                              "                     (c)                                                                              pyrido[3,2-f] O CH(CH.sub.3).sub.2                                                                         H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                     (d)                                                                              pyrido[3,2-f] O 4-ClC.sub.6 H.sub.4CH.sub.2                                                                H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                     (e)                                                                              pyrido[3,2-f] O 4-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                     (f)                                                                              pyrido[3,2-f] O 3,5-(OCH.sub.3).sub.2                                                                      H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                                        C.sub.6 HCH.sub.2                                          (g)                                                                              pyrido[3,2-f] O 3-CF.sub.3C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.                                                                              HClsub.2                                                                         "                     (h)                                                                              pyrido[3,2-f] O 4-NO.sub.2C.sub.6 H.sub.4CH.sub.2                                                          H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   26   pyrido[3,2-f] O CH.sub.3     H   S   Cl   (CH.sub.2).sub.2                                                                      -- "                   27   pyrido[3,2-f] S CH.sub.3     H   S   Cl   (CH.sub.2).sub.2                                                                      -- "                   28   pyrido[3,4-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   29   pyrido[3,4-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   30   pyrido[3,2-f] O CH.sub.3     H   O   CN   (CH.sub.2).sub.2                                                                      -- "                   31   pyrido[3,2-f] O C.sub.2 H.sub.5                                                                            H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   32   pyrido[3,2-f] S C.sub.2 H.sub.5                                                                            H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   33   7-Clpyrido    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                        [3,2-f]                                                                  34   7-Clpyrido    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                        [3,2-f]                                                                  35   pyrido[3,2-f] O C.sub.6 H.sub.11                                                                           H   O   Cl   CH.sub. 2                                                                             -- "                   36   pyrido[3,2-f] O CH.sub.2 C.sub.6 H.sub.5                                                                   H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   37   pyrido[3,2-f] O CH.sub.3     H   O   1-phtha-                                                                           (CH.sub.2).sub.2                                                                      -- "                                                             limido                              38   pyrido[3,2-f] S CH.sub.3     H   O   1-phtha-                                                                           (CH.sub.2).sub.2                                                                      -- "                                                             limido                              39   pyrido[3,2-f] S CH.sub.3     H   O   CN   (CH.sub.2).sub.2                                                                      -- "                   40   pyrido[3,2-f] O CH.sub.3     H   O   Cl                                                                                  ##STR28##                                                                            HCl                                                                              "                   41   pyrido[3,2-f] O CH.sub.3     CH.sub.3                                                                          O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   42   pyrido[3,2-f] O CH.sub.3     CH.sub.3                                                                          O   Cl   (CH.sub.2).sub.2                                                                      -- "                   43   pyrido[3,2-f] O CH.sub.3     H   O   Cl                                                                                  ##STR29##                                                                            HCl                                                                              "                   44   pyrido[3,2-f] S CH.sub.3     H   O   Cl                                                                                  ##STR30##                                                                            HCl                                                                              "                   45   pyrido[3,2-f] S CH.sub.3     H   O   Cl                                                                                  ##STR31##                                                                            HCl                                                                              "                   46                                                                                  ##STR32##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   47                                                                                  ##STR33##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   48                                                                                  ##STR34##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              "                   49                                                                                  ##STR35##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   50   benz          O CH(CH.sub.3).sub.2                                                                         H                                                                                  ##STR36##                                                                        Cl   CH.sub.2                                                                              -- "                   51   benz          O C.sub.2 H.sub.5                                                                            H                                                                                  ##STR37##                                                                        Cl   (CH.sub.2).sub.2                                                                      -- "                   52   6-Clpyrido    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                        [4,3-f]                                                                  53                                                                                  ##STR38##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   54                                                                                  ##STR39##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   55                                                                                  ##STR40##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   56                                                                                  ##STR41##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   57                                                                                  ##STR42##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   58                                                                                  ##STR43##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   59                                                                                  ##STR44##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   60                                                                                  ##STR45##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   61                                                                                  ##STR46##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   62                                                                                  ##STR47##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   63                                                                                  ##STR48##    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   64                                                                                  ##STR49##    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   65   pyrido[3,2-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      HCl                                                                              S(-)                66   pyrido[3,2-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- S(-)                67   pyrido[3,2-f] O CH.sub.3     H   O   Cl   (CH.sub.                                                                              HClsub.2                                                                         R(+)                68   pyrido[3,2-f] O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- R(+)                69   pyrido[3,2-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- S(+)                70   pyrido[3,2-f] S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- R(-)                71   7-Brpyrido    O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- Rac.                     [3,2-f]                                                                  72   7-Brpyrido    S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                        [3,2-f]                                                                  73   8-CH.sub.3pyrido                                                                            O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      H.sub.2 O                                                                        "                        [3,2-f]                                                                  74   8-CH.sub.3pyrido                                                                            S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      H.sub.2 O                                                                        "                        [3,2-f]                                                                  75   7-NO.sub.2benz-                                                                             O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   76   7-NO.sub.2benz-                                                                             S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   77   7-Fbenz-      O CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   78   7-Fbenz-      S CH.sub.3     H   O   Cl   (CH.sub.2).sub.2                                                                      -- "                   __________________________________________________________________________     .sup.(a) Rac = racemic mixture                                           

EXAMPLE 12-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onehydrochloride

A solution of 9 g (0.2 mole) of dimethylamine in 250 ml of ethanol wasadded to 24 g (0.1 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)one in asteel bomb. The mixture was heated at 100° C. for 18 hrs. The solutionwas concentrated in vacuo and the residue partitioned between ethylacetate and dilute sodium hydroxide. The ethyl acetate layer wasconcentrated and the residue comprised substantially of the free base ofthe title compound was dissolved in methyl isobutyl ketone-isopropanolmixture. The solution was acidified with hydrogen chloride gas to givethe title compound, m.p. 188°-197° C.

EXAMPLE 22-[2-(Dimethylamine)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one

All of the hydrochloride salt obtained in Example 1 was partitionedbetween chloroform and dilute sodium hydroxide and the chloroform layerconcentrated. The residue was crystallized several times from isopropylether to give 6 g (21%) of the free base, m.p. 56°-76° C.

Analysis: Calculated for C₁₄ H₂₀ N₂ O₂ : C, 67.72; H, 8.12; N, 11.28.Found: C, 67.35; H, 8.16; N, 11.09.

EXAMPLE 32,3-Dihydro-4-methyl-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate[1:1]

To 50 ml of morpholine was added 20 g (0.084 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one. Thesolution was refluxed for 5 hrs and then concentrated in vacuo. Theresidue was dissolved in chloroform, and the solution was washed withdilute sodium hydroxide, dried over sodium sulfate and concentrated invacuo. The residue comprised substantially of the free base of the titlecompound was reacted with 10.5 g (0.09 mole) of fumaric acid inisopropanol-water. The resulting solid was recrystallized fromisopropanol-water to give 21.5 g (64%), m.p. 199°-201° C.

Analysis: Calculated for C₂₀ H₂₆ N₂ O₇ : C, 59.10; H, 6.45; N, 6.89.Found: C, 58.95; H, 6.52; N, 6.88.

EXAMPLE 44-Benzyl-2,3-dihydro-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepin-5(4H)-one

To 200 ml of morpholine was added 30 g (0.095 mole) of4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5-(4H)-one. Thesolution was refluxed for 3 hrs and then concentrated in vacuo. Theresidue was partitioned between dilute sodium hydroxide and chloroform.The chloroform layer was dried over sodium sulfate and concentrated invacuo. The solid obtained was recrystallized from isopropyl ether-ethylacetate three times to give 15.2 g of solid (43%), m.p. 97°-99° C.

Analysis: Calculated for C₂₂ H₂₆ N₂ O₃ : C, 72.10; H, 7.15; N, 7.64.Found: C, 72.25; H, 7.22; N, 7.64.

EXAMPLE 54-Benzyl-2,3-dihydro-2-[2-(methylamino)-3-ethyl]-1,4-benzoxazepin-5(4H)-onefumarate[1:1]

A solution of 5.95 g (0.19 mole) of monomethylamine in 200 ml of ethanolwas added to 30 g (0.095 mole) of4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one in asteel bomb. The mixture was heated at 100° C. for 16 hr. The solutionwas concentrated in vacuo and the residue partitioned between chloroformand dilute sodium hydroxide. The chloroform layer was concentrated andthe residue comprised substantially of the free base of the titlecompound was dissolved in isopropanol and reacted with fumaric acid togive the fumarate. The salt was dried under vacuum at 100° C. untilentrapped isopropyl alcohol was removed, m.p. 178°-81° C.

Analysis: Calculated for C₂₃ H₂₆ N₂ O₆ : C, 64.77; H, 6.15; N, 6.57.Found: C, 64.87; H, 6.20; N, 6.62.

EXAMPLE 62-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)thionehydrochloride[1:1]

To a solution of 7.2 g (0.16 mole) of dimethylamine in 350 ml ofabsolute ethanol was added 20.4 g (0.08 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)thione.The solution was heated in a steel bomb for 18 hr at 100° C. and thenconcentrated. The residue was partitioned between chloroform and dilutesodium hydroxide. The chloroform layer was dried over sodium sulfate andconcentrated. The solid comprised substantially of the free base of thetitle compound was reacted with hydrogen chloride gas in ethanol to givethe hydrochloride salt. The salt was recrystallized from ethanol anddimethylformamide followed by three recrystallizations from ethanol togive 7.5 g (28%), m.p. 233°-236° C.

Analysis: Calculated for C₁₄ H₂₁ N₂ SOCl: C, 55.90; H, 7.04; N, 9.32.Found: C, 55.72; H, 7.26; N, 8.94.

EXAMPLE 74-Benzyl-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazepin-5(4H)-onemonohydrate

Following the procedure of Example 1,4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one anddimethylamine were reacted and the free base of the title compound wasobtained in the concentrated residue. Recrystallization fromethanol-water gave the product, m.p. 75°-77° C.

Analysis: Calculated for C₂₀ H₂₆ N₂ O₃ : C, 70.13; H, 7.65; N, 8.21.Found: C, 70.02; H, 7.53; N, 8.25.

EXAMPLE 82,3-Dihydro-4-methyl-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepine-5(4H)-thionehydrochloride[1.1]

A solution of 20.4 g (0.08 mole) of2,3-dihydro-4-methyl-2-(2-chloroethyl)-1,4-benzoxazepin-5(4H)-thione in60 ml of morpholine was refluxed for 5 hr. then concentrated. Theresidue was partitioned between dilute sodium hydroxide and chloroform.The chloroform layer was dried over sodium sulfate and concentrated togive a residue comprised substantially of the free base of the titlecompound. The hydrochloride salt was prepared in methyl isobutylketone-dimethylformamide solution with hydrogen chloride gas. The saltwas recrystallized from ethanol-dimethylformamide to give 14 g solid(51%), m.p. 253°-256° C.

Analysis: Calculated for C₁₆ H₂₃ N₂ SO₂ Cl: C, 56.04; H, 6.76; N, 8.17.Found: C, 55.73; H, 6.63; N, 7.97.

EXAMPLE 92-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,3-f][1,4]-oxazepin-5(4H)-oneoxalate[1:1]

A steel bomb was charged with 5.0 g (0.017 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepin-5(4H)-one,50 ml of absolute ethanol and 3.78 g (0.034 mole) of dimethylamine as40% aqueous solution. The bomb was heated at 100° C. for 16 hr.Volatiles were removed under reduced pressure and the residuepartitioned between chloroform and 15% aqueous sodium hydroxide. Thechloroform layer was washed twice with water, dried over magnesiumsulfate and concentrated under reduced pressure to give 2.7 g (54%) ofviscous yellow oil comprised substantially of the free base of the titlecompound. The oil was dissolved in isopropyl alcohol and reacted withoxalic acid. The oxalate salt was recrystallized from ethanol-water,m.p. 192°-194° C.

Analysis: Calculated for C₂₀ H₂₄ N₂ O₆ : C, 61.84; H, 6.23; N, 7.21.Found: C, 61.41; H, 6.27; N, 7.09.

EXAMPLE 102-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate[2.3]

To 90 g (0.8 mole) of 40% aqueous dimethylamine in a steel bomb wasadded 25 g (0.09 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride. The mixture was heated to 100° C. for 15 hr under mildagitation. The mixture was partitioned using dilute sodium hydroxide andtwo chloroform extractions. The chloroform layers were combined andconcentrated. The residue comprised substantially of the free base ofthe title compound was dissolved in 200 ml of isopropyl alcohol and 9 gof oxalic acid added. The oxalate salt was recrystallized from 95%ethanol to give 18 g. The oxalate salt was then converted to the freebase by partitioning between chloroform and dilute sodium hydroxide andevaporating the chloroform layer. The residue, the free base of thetitle compound, was dissolved in isopropyl alcohol and reacted withfumaric acid to give 13 g of white solid (34%), m.p. 146°-148° C.

Analysis: Calculated for C₁₉ H₂₅ N₃ O₈ : C, 53.90; H, 5.90; N, 9.92.Found: C, 53.76; H, 6.02; N, 9.96.

EXAMPLE 112-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionefumarate compound with ethanol[1:1:0.5]

To a solution of 32.8 g (0.29 mole) of 40% aqueous dimethylamine and 100ml of ethanol in steel bomb was added 15 g (0.058 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione.The mixture was heated to 100° C. for 18 hr under mild agitation. Thesolution was cooled and partitioned between chloform and dilute sodiumhydroxide. The chloroform layer was dried over sodium sulfate andconcentrated. The residue comprised substantially of the free base ofthe title compound was dissolved in isopropyl alcohol and reacted with 7g of fumaric acid. The fumarate salt was recrystallized from isopropylalcohol to give 19 g (86%), m.p. 105°-129° C. A 14 g sample of the saltwas recrystallized from ethanol to give 10.5 g yellow solid, m.p.103°-118° C. The NMR spectra indicates the crystals contains 1/2 moleethanol.

Analysis: Calculated for C₃₆ H₅₂ N₆ O₁₁ S₂ : C, 53.45; H, 6.48; N,10.39. Found: C, 53.07; H, 6.53; N, 10.23.

EXAMPLE 122-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionefumarate[1:1]

To a solution of 113 ml (1.0 mole) of 40% aqueous dimethylamine and 326ml of ethanol in a steel bomb was added 48.4 g (0.189 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione.The mixture was heated at 100° C. for 14 hr. The ethanol was removed ina rotary evaporator leaving some water in the residue. The residue wasdissolved in 200 ml of methylene chloride and washed with three 100 mlportions of 20% aqueous potassium carbonate solution. The combinedaqueous layers were extracted with three 150 ml portions of methylenechloride. Methylene chloride solutions were combined and treated withcharcoal. Charcoal was filtered off and the filtrate was evaporated togive an oil. The oil was dissolved in 215 ml isopropyl alcohol and thesolution was heated to a slow boil. A solution of 21.9 g (0.19 mole) offumaric acid in 150 ml of boiling methanol was added to the isopropylalcohol solution. Crystalline solid was obtained weighing 63.4 g (88%).The solid was recrystallized from hot 200 proof ethyl alcohol. Thecrystals were filtered off and triturated in isopropyl ether at roomtemperature and again separated by filtering. After drying in a vacuumoven overnight at 85° C., crystals in the amount of 72.45 g (79%), m.p.130°-133° C., were obtained.

Analysis: Calculated for C₁₇ H₂₃ N₃ O₅ S: C, ;b 53.53; H, 6.08; N,11.02. Found: C, 53.23; H, 6.11; N, 10.64.

EXAMPLE 134-Benzyl-2,3-dihydro-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepine-5(4H)-thione

To a suspension of a finely ground mixture of 2.9 g (0.013 mole) ofphosphorus pentasulfide and 2.9 g of potassium sulfide in 75 ml of drytoluene was added 12 g (0.033 mole) of4-benzyl-2,3-dihydro-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepine-5(4H)-one.The mixture was stirred at reflux for 10 hr. and filtered. The filratewas concentrated and the residue crystallized from isopropylether-toluene to give 2.54 g (20%), m.p. 236°-238° C.

Analysis: Calculated for C₂₂ H₂₆ N₂ O₂ S: C, 69.08; H, 6.85; N, 7.32.Found: C, 69.60; H, 6.96 N, 7.15.

EXAMPLE 142,3-Dihydro-4-methyl-2-[2-(methylamino)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate[1:1]

Following the procedure of Example 5, 50 g (0.21 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one and13.0 g (0.42 mole) of monomethylamine (in 400 ml ethanol) were reactedto give the free base of the title compound which was reacted withfumaric acid to give, after isolation and recrystallization from ethylalcohol, 17 g (23%) of the title compound, m.p. 154°-156° C.

Analysis: Calculated for C₁₇ H₂₂ N₂ O₆ : C, 58.27; H,6.33; N, 8.00.Found: C, 58.34; H, 6.52; N, 7.82.

EXAMPLE 152,3-Dihydro-4-methyl-2-[2-(methylamino)ethyl]-1,4-benzoxazepin-5(4H)-one

2,3-Dihydro-4-methyl-2-[2-(methylamino)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate was converted back to the free base by partitioning in dilutesodium hydroxide and chloroform. Evaporation of the chloroform layer anddistilling, b.p. 182°/0.2 mm, gave 4.3 g of the product.

Analysis: Calculated for C₁₃ H₁₈ N₂ O₂ : C, 66.64; H, 7.74; N, 11.96.Found: C, 66.48; H, 7.69; N, 11.88.

EXAMPLE 162,3-Dihydro-2-[2-(4-hydroxy-4-phenyl)-piperidinylethyl]-4-methyl-1,4-benzoxazepine-5(4H)-thione(and hydrochloride salt)

A suspension of 10.7 g (0.078 mole) of potassium carbonate, 13.7 g(0.078 mole) of 4-hydroxy-4-phenylpiperidine and 19.8 g (0.078 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in200 ml of n-butanol was refluxed overnight. The mixture was filtered andthe filtrate concentrated in vacuo. The residue was dissolved inethanol-ligroin and reacted with hydrogen chloride gas to give thehydrochloride salt which was recrystallized fromethanol-dimethylformamide. The hydrochloride salt was converted back tothe free base by partitioning in chloroform and dilute sodium hydroxideand evaporating the chloroform. Recrystallization twice from isopropylalcohol gave 9.27 g (30%) product free base, m.p. 142°-148° C.

Analysis: Calculated for C₂₃ N₂₈ N₂ O₂ S: C, 69.66; H, 7.12; N, 7.07.Found: C, 69.78; H, 7.18; N, 7.00.

EXAMPLE 172,3-Dihydro-4-methyl-2-[2-[1-(4-phenyl-1,2,3,6-tetrahydro)pyridinyl]ethyl]-1,4-benzoxazepine-5(4H)thione

A suspension of 24.3 g (0.176 mole) of potassium carbonate, 11.5 g(0.059 mole) of 4-phenyl-3,4-tetrahydropyridine and 15 g (0.059 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thioneand enough n-butanol to form a slurry were refluxed for 72 hr. Thereaction mixture was filtered hot and the filtrate cooled to roomtemperature and refiltered. The last filtrate was concentrated and theresidue dissolved in ethyl acetate. The crystals obtained on coolingwere recrystallized from ethyl acetate to give 7 g of product (31%),m.p. 153°-155° C.

Analysis: Calculated for C₂₃ H₂₆ N₂ OS: C, 72.98; H, 6.92; N, 7.40.Found: C, 73.36; H, 7.01; N, 7.47.

EXAMPLE 188-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thionehydrochloride[1:1]

A solution of 9.8 g (0.04 mole) of8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol and 10 ml of a 40% aqueoussolution of dimethylamine were mixed and heated in a steel bomb at 100°C. for 16 hr. The ethanol was evaporated under reduced pressure and theresidue dissolved in chloroform and partitioned with 10% sodiumhydroxide solution. The chloroform layer was evaporated under reducedpressure to give an amorphous solid. The solid was dissolved in 6Nhydrochloric acid and the solution washed with ethyl acetate. Theaqueous layer was basified with 50% sodium hydroxide and extracted withethyl acetate. The ethyl acetate layer was evaporated under reducedpressure to give a viscous oil comprised substantially of the free baseof the title compound which was dissolved in absolute ethanol andreacted with ethereal hydrogen chloride. The hydrochloride salt wasrecrystallized from ethanol to give 30 g (25%) product, m.p. 196°-199°C.

Analysis: Calculated for C₁₄ H₂₀ N₂ Cl₂ OS: C, 50.15; H, 6.01; N, 8.35.Found: C, 50.15; H, 6.18; N, 8.07.

EXAMPLE 198-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-oneoxalate[1:1]

A solution of 10 g (0.037 mole) of8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 50 ml of absolute ethanol and 10 ml of 40% aqueous solution ofdimethylamine were mixed and heated in a steel bomb at 100° C. for 16hr. The solution was concentrated under reduced pressure and the residuedissolved in chloroform and partitioned with 15% sodium hydroxide (2washes). The chloroform layer was dried over magnesium sulfate andevaporated under reduced pressure to give an oil, comprisedsubstantially of the free base of the title compound. The oil wasdissolved in absolute ethanol and reacted with oxalic acid. The oxalatesalt was recrystallized from ethanol in the amount of 4 g (38%), m.p.198°-201° C.

Analysis: Calculated for C₁₈ H₂₁ N₂ ClO₆ : C, 51.55; H, 5.68; N, 7.51.Found: C, 51.07; H, 5.69; N, 7.43.

EXAMPLE 207-Bromo-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-oneoxalate[1:1]

To a solution of 3.0 g (0.01 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 50 ml of absolute ethanol was added 2.2 ml of a 40% aqueous solutionof dimethylamine. The reaction mixture was heated in a stainless steelbomb at 100° C. for 16 hr and concentrated under reduced pressure. Theresidue was partitioned between chloroform and 15% sodium hydroxidesolution. The chloroform layer was separated and extracted with 3Naqueous hydrochloric acid. The acid layer was basified with 50% aqueoussodium hydroxide and extracted with chloroform. The chloroform wasevaporated under reduced pressure to give 2.4 g (73%) viscous brown oil,the free base of the title compound. The oil was dissolved in isopropylalcohol and reacted with oxalic acid. The oxalate salt wasrecrystallized from isopropyl alcohol/water to give the title salt, m.p.192°-194° C.

Analysis: Calculated for C₁₆ H₂₁ O₆ BrN₂ : C, 46.06; H, 5.07; N, 6.71.Found: C, 46.00; H, 5.10; N, 6.68.

EXAMPLE 212-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-oneoxalate[1:1]

A solution of 8 g (0.028 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-oneand 6.2 g of 40% dimethylamine (0.055 mole) in 100 ml of ethanol washeated in a steel bomb to 100° C. for 18 hr. The resulting solution waspartitioned between methylene chloride and dilute sodium hydroxidesolution. The methylene chloride layer was dried over sodium sulfate andconcentrated. The residue comprised substantially of the free base ofthe title compound was dissolved in isopropyl alcohol and reacted with2.6 g oxalic acid. The oxalate salt obtained was recrystallized fromisopropyl alcohol in water, m.p. 206°-209° C.

Analysis: Calculated for C₂₀ H₂₄ N₂ O₆ : C, 61.85; H, 6.23; N, 7.21.Found: C, 61.61; H, 6.26; N, 7.13.

EXAMPLE 22

When in the procedure of Example 10 equal molar amounts of the followingare substituted for2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride:

2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepin-5(4H)-onehydrochloride, and

2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[2,3-f][1,4]-oxazepin-5(4H)-onehydrochloride,

there are obtained:

2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-onefumarate,

2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepin-5(4H)-onefumarate, and

2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[2,3-f][1,4]-oxazepin-5(4H)-onefumarate.

EXAMPLE 232-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepine-5(4H)-thionehydrochloride[2:3]

To a solution of 0.5 g (0.002 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepine-5(4H)-thionein 20 ml of ethyl alcohol was added 2 ml of 40% aqueous dimethylamine.The mixture was heated in a steel bomb to 100° C. for 14 hr. Theresulting solution was filtered and concentrated. The residue wasdissolved in isopropyl alcohol and a few drops of ethereal hydrogenchloride were added. The hydrochloride salt crystals were recrystallizedby dissolving in ethyl alcohol and boiling while replacing the ethylalcohol with isopropyl alcohol. The yield of product was 0.3 g (47%),m.p.: decomp. above 200° C.

Analysis: Calculated for C₂₆ H₄₁ N₆ O₂ S₂ Cl₃ : C, 48.78; H, 6.46; N,13.13. Found: C, 49.34; H, 6.47; N, 13.03.

EXAMPLE 242-[2-(Diethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneand diethylamine in ethanol are heated together to obtain the titlecompound.

EXAMPLE 252-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,3-f][1,4]-oxazepine-5(4H)thioneoxalate[1:1]hemihydrate

To a solution of 15 g (0.05 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]-oxazepine-5(4H)-thionein 50 ml of absolute ethanol was added 10 ml of a 45% aqueous solutionof dimethylamine. The solution was heated in a steel bomb for 16 hr. Theethanol was evaporated under reduced pressure and the residuepartitioned between chloroform and 15% aqueous sodium hydroxide. Thechloroform layer was separated and extracted with 3N aqueoushydrochloric acid. The acid layer was basified with 50% aqueous sodiumhydroxide and extracted with chloroform. The chloroform solution wasconcentrated under reduced pressure and the residue was dissolved inisopropyl alcohol and reacted with oxalic acid. The salt wasrecrystallized from isopropyl alcohol and water to give the titlecompound, m.p. 115°-118° C.

Analysis: Calculated for C₄₀ H₅₀ N₄ O₁₁ S₂ : C, 58.09; H, 6.09; N, 6.77.Found: C, 58.42; H, 5.85; N, 6.70.

EXAMPLE 262-[2-(Dimethylamino)ethyl]-2,3-dihydro-7,9-diiodo-4-methyl-1,4-benzoxazepin-5(4H)-one

Utilizing the procedures of Example 1 and 2 and substituting2-(2-chloroethyl)-7,9-diiodo-4-methyl-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onefor 2-(chloroethyl)-4-methyl-2,3-dihydro-1,4-benzoxazepin-5(4H)-one, thetitle compound is obtained.

EXAMPLE 277-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-oneoxalate[1:1]

To a solution of 9.0 g (0.033 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-onein 50 ml absolute ethanol was added 7 g (0.066 mole) of a 45% aqueoussolution of dimethylamine. The solution was heated in a stainless steelbomb at 100° C. for 14 hr. The reaction mixture was concentrated underreduced pressure and the residue was partitioned between chloroform and15% aqueous sodium hydroxide. The chloroform layer was separated andevaporated under reduced pressure to give a viscous brown oil. The oilwas dissolved in isopropyl alcohol and oxalic acid added.Recrystallization from isopropyl alcohol/water gave 7.0 g (57%) oxalatesalt, m.p. 199°-200° C.

Analysis: Calculated for C₁₆ H₂₁ N₂ O₆ Cl: C, 51.55; ,5.68; N, 7.51.Found: C, 51.52; H, 5.72; N.7.44.

EXAMPLE 282-(Dimethylamino)methyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one

When in the procedure of Example 10,2-chloromethyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneis substituted for2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one,the title compound is prepared and is isolated if desired as apharmaceutically acceptable salt.

EXAMPLE 292-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionemethiodide

2-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionefumarate[1:1], ethanol[2:1], 3.8 g (0.01 mole) was partitioned betweenchloroform and dilute sodium hydroxide. The chloroform extract was driedover sodium sulfate and concentrated. The residue was dissolved in 15 mlof methyl isobutyl ketone and added to a solution of 1.4 g (0.01 mole)of methyl iodide in 15 ml of isobutyl ketone. Recrystallization from 50%ethanol--50% methyl isobutyl ketone gave 2.5 g (78%) of the product,m.p. 221°-225° C.

Analysis: Calculated for C₁₄ H₂₂ N₃ OSI: C, 41.28; H, 5.44; N, 10.31.Found: C, 41.29; H, 5.51; N, 10.30.

EXAMPLE 307-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thioneoxalate[1:1]hemihydrate

To a solution of 8.0 g (0.027 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)thionein 50 ml of absolute ethanol was added 6 ml (0.054 mole) of 40% aqueoussolution of dimethylamine. The solution was heated in a steel bomb at90° C. for 14 hr. The ethanol was removed under reduced pressure and theresidue was partitioned between chloroform and aqueous sodium hydroxide.The chloroform layer was concentrated to give a viscous yellow oil. Theoil was dissolved in isopropyl alcohol and reacted with oxalic acid. Theoxalate salt immediately precipitated. The mixture was heated and asmall amount of water was added to dissolve the salt. A whitecrystalline powder was obtained, m.p. 150°-151° C.

Analysis: Calculated for C₃₂ H₄₄ N₄ Cl₂ O₁₁ S₂ : C, 48.30; H, 5,57; N,7.04. Found: C, 48.74; H, 5.34; N, 6.95.

EXAMPLE 312-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,1-f][1,4]-oxazepine-5(4H)-thionehydrochloride[1:1]

To a solution of 15.0 g (0.05 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]-oxazepine-5(4H)-thionein 50 ml of absolute ethanol was added 10 g of a 40% aqueous solution ofdimethylamine. The resulting solution was heated in a steel bomb at 100°C. for 40 hr and concentrated under reduced pressure. The residue waspartitioned between 15% aqueous sodium hydroxide and chloroform. Thechloroform layer was evaporated and the residue partitioned between 3Nhydrochloric acid and chloroform. The aqueous layer was made alkalinewith 50% sodium hydroxide and extracted with chloroform. The chloroformextract was concentrated and the residue dissolved in isopropyl alcohol.Ethereal hydrogen chloride was added. Recrystallization of theprecipitate from isopropyl alcohol/water gave 3.0 g (20%) of theproduct, m.p. 238°-240° C.

Analysis: Calculated for C₁₈ H₂₃ N₂ ClOS: C, 61.61; H, 6.61; N, 7.98.Found: C, 61.80; H, 6.61; N, 7.91.

EXAMPLE 32

When in the procedure of Example 11 equal molar amounts of the followingare substituted for2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione:

2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepine-5(4H)-thione,and

2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[2,3-f][1,4]-oxazepine-5(4H)-thione,

there are obtained:

(a)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepine-5(4H)-thionefumarate, and

(b)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[2,3-f][1,4]-oxazepine-5(4H)-thionefumarate.

EXAMPLE 332-[2-(Dimethylamino)ethyl]-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-oneoxalate[1:1]hemihydrate

To a solution of 3.0 g (0.011 mole) of2-(2-chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-onein 50 ml of absolute ethanol was added 3.0 g of a 40% aqueous solutionof dimethylamine. The reaction mixture was heated in a stainless steelbomb at 100° C. for 16 hr, cooled and evaporated under reduced pressure.The residue was partitioned between chloroform and 15% sodium hydroxidesolution. The chloroform layer was concentrated and the residue, thefree base, was dissolved in isopropyl alcohol and reacted with oxalicacid. The resulting oxalate salt was recrystallized from isopropylalcohol/H₂ O to give 1.9 g (45%) of the title salt, m.p. 176°-178° C.

Analysis: Calculated for C₃₄ H₅₀ N₄ O₁₅ : C, 54.10; H, 6.67; N, 7.42.Found: C, 54.29; H, 6.59; N, 7.53.

EXAMPLE 347-Bromo-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thioneoxalate[1:1]monohydrate

To a solution of 13 g (0.04 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)thionein 50 ml of absolute ethanol was added 8 ml of a 45% aqueous solution ofdimethylamine. The solution was heated at 100° C. in a steel bomb for 16hr. The ethanol was evaporated under reduced pressure and the residuepartitioned between ethyl acetate and 3N aqueous hydrochloric acid. Theaqueous extract was basified with 50% aqueous sodium hydroxide andextracted with chloroform. The chloroform was concentrated under reducedpressure. The residue, the free base of the title compound, wasdissolved in isopropyl alcohol and reacted with oxalic acid. The oxalatesalt was recrystallized from 95% ethanol to give the title salt, m.p.155°-157° C.

Analysis: Calculated for C₃₂ H₄₆ N₄ Br₂ O₁₂ S₂ : C, 42.58; H, 5.14; N,6.12. Found: C, 42.93; H, 4.79 N, 6.19.

EXAMPLE 35a to h

When in the procedure of Example 27, equal molar amounts of thefollowing are substituted for7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one

2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-1,4-benzoxazepin-5(4H)-one,

2-(2-chloroethyl)-2,3-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-one,

2-(2-chloroethyl)-2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5(4H)-one,

2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one

2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)-1,4-benzoxazepin-5(4H)-one

2-(3-chloroethyl)-2,3-dihydro-4-(3,5-dimethoxybenzyl)-1,4-benzoxazepin-5(4H)-one,

2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)-1,4-benzoxazepin-5(4H)-one,and

2-(2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)-one,

there are obtained:

(a)4-cyclohexyl-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazepin-5(4H)-oneoxalate,

(b)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-oneoxalate,

(c)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5(4H)-oneoxalate,

(d)4-(4-chlorobenzyl)-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazepin-5(4H)-oneoxalate,

(e)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-methylbenzyl)-1,4-benzoxazepin-5(4H)-oneoxalate,

(f)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(3,5-dimethoxybenzyl)-1,4-benzoxazepin-5(4H)-oneoxalate,

(g)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-[(3-(trifluoromethyl)benzyl]-1,4-benzoxazepin-5(4H)-oneoxalate, and

(h)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)-oneoxalate.

EXAMPLE 36a to h

When in the procedure of Example 10, equal molar amounts of thefollowing are substituted for2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-ethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-isopropylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-4-(4-chlorobenzoyl)-2,3-dihydropyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-(4-methoxybenzyl)pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride, and

2-(2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onehydrochloride,

there are obtained:

(a)4-cyclohexyl-2-[2-(dimethylamino)ethyl]-2,3-dihydropyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(b)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-ethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(c)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-isopropylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(d)4-(4-chlorobenzyl)-2-[2-(dimethylamino)ethyl]-2,3-dihydro-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(e)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-methylbenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(f)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-methoxybenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate,

(g)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(3-trifluoromethylbenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate, and

(h)2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitrobenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate.

EXAMPLE 37a to d

When in the procedure of Example 3, equal molar amounts of the followingare substituted for morpholine:

pyrrolidine,

piperidine,

piperazine, and

4-methyl-piperazine; there are obtained:

(a)2,3-dihydro-4-methyl-2-[2-(1-pyrrolidino)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate,

(b)2,3-dihydro-4-methyl-2-[2-(1-piperidino)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate,

(c)2,3-dihydro-4-methyl-2-[2-(1-piperazino)ethyl]-1,4-benzoxazepin-4(4H)-onefumarate, and

(d)2,3-dihydro-4-methyl-2-[2-(4-methylpiperazin-1-yl)ethyl]-1,4-benzoxazepin-5(4H)-onefumarate.

EXAMPLE 382-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepin-5(4H)-onedihydrochloride

A solution of 1.5 g (0.0058 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepin-5(4H)-onein 20 ml of dimethylamine was stirred at 25° C. in a sealed containerfor 72 hr. The excess dimethylamine was allowed to evaporate and theresidue was partitioned between chloroform and dilute sodium hydroxide.The chloroform layer was concentrated and the residue, the free base ofthe title compound, was dissolved in isopropyl alcohol and reacted withhydrogen chloride. The resulting hydrochloride salt weighted 1.5 g(77%), m.p.>250° C.

Analysis: Calculated for C₁₃ H₂₁ N₃ OSCl₂ : C, 46.16; H, 6.27 N, 12.42.Found: C, 45.68; H, 6.18; N, 12.35.

EXAMPLE 392-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepine-5(4H)-thioneoxalate

A solution of 1.5 g (0.005 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepine-5(4-H)thionein 40 ml of dimethylamine was stirred at 25° C. in a sealed containerfor 96 hr. The dimethylamine was allowed to evaporate and the residuewas partitioned between methylene chloride and dilute sodium hydroxide.The chloroform layer was concentrated and the residue, the free base ofthe title compound, was reacted with 0.4 g oxalic acid in a solution of30 ml of 90-100 isopropyl alcohol water. The resulting crystals wererecrystallized from the same solvent to give 1 g of the product, m.p.191°-193° C.

Analysis: Calculated for C₁₅ H₂₁ N₃ S₂ O₄ : C, 48.50; H, 5.70; N, 11.33.Found: C, 48.49; H, 5.84; N, 10.99.

EXAMPLE 402-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-oneoxalate (1:2) hemihydrate

A solution of 5 g (0.02 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one,in 25 ml of dimethylamine was placed in a sealed vessel and stirred for72 hr. The vessel was opened and the excess dimethylamine allowed toevaporate. The residue was dissolved in chloroform and the solvent wasstripped off in vacuo to remove excess dimethylamine. The residue waspartitioned between dilute sodium hydroxide and ethyl acetate. The ethylacetate solution was concentrated and the residue was treated with 3 g(0.033 mole) of oxalic acid in 50 ml of isopropyl alcohol and enoughwater to dissolve the salt while boiling. The resulting crystals wererecrystallized from the same solvent. Yield of product was 5.3 g (60%),m.p. 179°-181° C.

Analysis: Calculated for C₃₄ H₄₈ N₆ O₂₁ : C, 46.48; H, 5.52; N, 9.58.Found: C, 46.58; H, 5.70 N, 9.61.

EXAMPLE 412-2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepine-5(4H)-thioneoxalate (1:2)

A 4 g (0.009 mole) sample of2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-oneoxalate (1:2) hemihydrate was partitioned between dilute sodiumhydroxide and chloroform. The aqueous layer was extracted three timesand the combined chloroform extracts were dried over sodium sulfate andconcentrated. The residue was dissolved in 200 ml of dry toluene andagain concentrated in vacuo to effect drying. The residue was dissolvedin dry pyridine (10 ml) and treated with 2.8 g (0.01 mole) of phosphoruspentasulfide. The mixture was stirred at reflux for 20 hr. The cooledmixture was partitioned between dilute sodium hydroxide and chloroform.The aqueous layer was extracted three times with chloroform. Thecombined chloroform extracts were dried over sodium sulfate andconcentrated. One gram of the residue was treated with 0.6 g of oxalicacid in isopropyl alcohol/10% water. The resulting crystals werecollected by filtration. Yield of oxalate salt was 0.37 g., m.p.111°-114° C.

Analysis: Calculated for C₁₇ H₂₃ N₃ SO₉ : C, 45.84; H, 5.20; N, 9.43.Found: C, 45.46; H, 5.38 N, 9.28.

EXAMPLE 422-(2-Aminopropyl)-2,3-dihydro-4-methyl-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one,oxalate[1:1]

2,3-Dihydro-4-methyl-5(4H)-oxopyrido[3,2-f][1,4]oxazepine-2-propanenitrile,5 g (0.22 mole, in 150 ml of ethanol was treated with about 1.5 g of wetRaney nickel. The mixture was hydrogenated in a Parr apparatus at 60° C.and 40 psi. The mixture was cooled and filtered and the filtrateconcentrated. The residue was treated with 3.9 g of oxalic acid in 130ml of boiling isopropyl alcohol containing 2 ml of water. The hotsolution was filtered and allowed to cool. The resulting solid wasrecrystallized from ethanol. Yield of oxalate hemihydrate was 3 g (43%),m.p. 126°-134° C.

Analysis: Calculated for C₂₈ H₄₀ N₆ O₇ : , 50.30; H, 6.03 N, 12.57.Found: C, 50.46; H, 5.71; N, 12.21.

EXAMPLE 432,3-Dihydro-4-methyl-2-[2-(4-morpholinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-onemaleate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 16 g (058 mole) was dissolved in morpholine (30 mL) andstirred overnight at room temperature. To the solution was added dilutesodium hydroxide solution (50 ml) and the resulting mixture extractedwith chloroform (3×30 ml). The chloroform was removed on the rotaryevaporator with aspiration. The residual morpholine was removed in vacuoat 50° C. (rotary evaporator). To the residual free base (15.5 g, 0.053mole) was added isopropyl alcohol (1 liter) and maleic acid (9.24 g g,0.080 mole). The mixture was heated to boiling and the clear solutioncooled at 20° C. for several hours. The resulting crystals, 16 g(68.1%), were recrystallized from isopropyl alcohol, m.p. 163°-165° C.

Analysis: Calculated for C₁₉ H₂₅ N₃ O₇ : C, 56.01; H, 6.18; N, 10.31.Found: C, 55.71; H, 6.21; N, 10.18.

EXAMPLE 442,3-Dihydro-4-methyl-2-[2-(1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate[1:1]

A sample of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-onehydrochloride, 16 g (0.058 mole), was dissolved in 65 ml of pyrrolidine.The stirred solution was heated to 80° C. for 3 hr. The solution wascooled to room temperature and dilute sodium hydroxide solution (50 ml)was added. The resulting solution was extracted with chloroform (3×30ml) and concentrated in vacuo. The residue was taken up in boilingisopropyl alcohol (500 ml/ and fumaric acid (9.2 g, 0.079 mole) wasadded. The solution was filtered hot and the filtrate cooled to 20° C.for several hours. The resulting crystals, 14 g (47.8%) were collectedand recrystallized from isopropyl alcohol, m.p. 147°-149° C.

Analysis: Calculated for C₂₃ O₁₀ N₃ H₂₉ : C, 54.43; H, 5.76; N, 8.28.Found: C, 54.38; H, 5.83; N, 8.27.

EXAMPLE 452-[2-(Dibutylamino)ethyl]-2,3-dihydro-4-methyl-pyrido[3,2-f][1,4]oxazepin-5(4H)-onemaleate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-onehydrochloride, 16 g (0.058 mole) was dissolved in dimethylformamide (30ml) and di-n-butylamine (30 ml). The solution was stirred at 90° C. for3 hr at 100° C. for 2.5 hr. The solution was cooled and to it was added50 ml of dilute sodium hydroxide solution. The resulting mixture wasextracted with chloroform (3×50 ml). The chloroform was removed on therotary evaporator with water aspiration at 50° C. Residualdimethylformamide and d-n-butylamine were removed at low vacuum and 50°C. (rotary evaporator). To the residual free base, 13.8 g (0.041 mole)was added isopropyl alcohol (900 ml) and oxalic acid, 5.6 g (0.062 mole)and the solution heated to boiling. The clear solution was cooledovernight at 20° C. and filtered to give 13.6 g (56.5%) of crystalswhich were recrystallized from isopropyl alcohol, m.p. 195°-196° C.

Analysis: Calculated for C₂₁ H₃₃ N₃ O₆ : C, 59.59; H, 7.85; N, 9.72.Found: C, 59.37; H, 7.91; N, 9.86.

EXAMPLE 462-[2-(Diethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 16 g (0.058 mole) was suspended in diethylamine (30 ml).The suspension was stirred for 72 hr at room temperature. The massspectrum indicated that the reaction had progressed 33% at this point.The mixture was then heated to reflux for 6 hr. Diethylamine was removedby rotary evaporation (70° C., water aspirator). The residue was takenup in chloroform (100 ml) and washed with dilute aqueous sodiumhydroxide (2×30 ml). The organic layer was concentrated by rotaryevaporation (70° C., water aspirator). The residue was dissolved inboiling isopropyl alcohol and treated with oxalic acid. Upon cooling,18.6 g (87.7%) of light brown crystals were collected (m.p. 150°-155°C.). A sample was recrystallized three more times from isopropylalcohol, m.p. 156°-157° C.

Analysis: Calculated for C₁₇ H₂₅ N₃ O₆ : C, 55.57; H, 6.86; N, 11.43.Found: C, 55.28; H, 6.85; N, 11.27.

EXAMPLE 472,3-Dihydro-4-methyl-2-[2-(1-piperidinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 4 g (0.015 mole) was dissolved in piperidine (30 ml) andheated to 80° C. with stirring for 20 minutes. The piperidine wasremoved by rotary evaporation (85° C., vacuum pump) and the residuetaken up in chloroform (50 ml). The organic layer was washed with diluteaqueous sodium hydroxide (2×20 ml) and concentrated by rotaryevaporation (80° C., water aspirator). The resulting oil was taken up inhot isopropyl alcohol and treated with oxalic acid. Upon cooling,crystals of the oxalate salt were collected and recrystallized fromisopropyl alcohol, to give 3.4 g (62%) of pale brown crystals, m.p.133°-136° C.

Analysis: Calculated for C₁₈ H₂₅ N₃ O₆ : C, 56.98; H, 6.64; N, 11.07.Found: C, 56.95; H, 6.87; N, 10.79.

EXAMPLE 482,3-Dihydro-4-methyl-2-[2-[methyl(phenylmethyl)amino]ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-onemaleate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-b5(4H)-one hydrochloride, 4 g (0.015 mole) was dissolved in methyl benzylamine (30 ml) and heated to 80° C. with stirring. After three hours, theexcess amine was removed by rotary evaporation (90° C., vacuum pump).The residual oil was taken up on chloroform (40 ml) and washed withdilute aqueous sodium hydroxide (30 ml). The chloroform layer wasconcentrated by rotary evaporation (90° C., water aspirator). Theresidual oil was dissolved in hot isopropyl alcohol and treated withmaleic acid. Upon cooling, 4.23 g (66%) of pale brown crystals werecollected, m.p. 167°-169° C.

Analysis: Calculated for C₂₃ H₂₇ N₃ O₆ : C, 62.57; H, 6.16; N, 9.52.Found: C, 62.28; H, 6.16; N, 9.24.

EXAMPLE 492,3-Dihydro-4-methyl-2-[2-(methylphenylamino)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-one

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 4.00 g (0.015 mole) was dissolved in N-methylaniline (30ml) and heated to 95° C. with stirring for 2 days. ExcessN-methylaniline was removed by rotary evaporation (95° C., vacuum pump).The residue was taken up in chloroform (80 ml) and washed with diluteaqueous sodium hydroxide (30 ml). The chloroform layer was decolorizedwith activated carbon and dried over sodium sulfate, filtered andconcentrated by rotary evaporation. The remaining residue was dissolvedin ethyl acetate (50 ml) and purified by high pressure liquidchromatography using a silica gel column and ethyl acetate as theeluent. After purification, crystals formed from ethyl acetate. Thesecrystals were recrystallized from ethyl acetate, giving 1.40 g (31%) ofpale brown crystals.

Analysis: Calculated for C₁₈ H₂₁ N₃ O₂ : C, 69.43; H, 6.79; N, 13.49.Found: C, 69.31; H, 6.77; N, 13.54.

EXAMPLE 502-[2-(2,5-Dimethyl-1-pyrrolidinyl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onefumarate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one,5.0 g (0.021 mole), was dissolved in 25 ml of absolute ethanol and 3 g(0.03 mole) of 2,5-dimethylpyrrolidine was added. The solution washeated to 75° C. for 48 hrs with stirring. Because the reaction wasincomplete at this time, an additional amount of 2,5-dimethylpyrrolidine(1.00 g, 0.01 mole) was added and the reaction continued. After 5 days,the reaction was still incomplete and more 2,5-dimethylpyrrolidine (1.00g, 0.01 mole) was added. The reaction appeared complete 2 days later.Solvent was removed by rotary evaporation (80° C., water aspirator).Excess 2,5-dimethylpyrrolidine was removed by rotary evaporation (80°C., vacuum pump). The residue was taken up in chloroform (200 ml) andwashed with dilute aqueous sodium hydroxide (2×75 ml). The organic layerwas dried over sodium sulfate, filtered, and concentrated by rotaryevaporation (70° C., water aspirator). The resulting oil was dissolvedin hot isopropyl alcohol and treated with fumaric acid. Upon cooling,2.38 g (27.4%) of pale brown crystals was collected, m.p. 161°-162° C.

Analysis: Calculated for C₂₁ H₂₉ N₃ O₆ : C, 60.13; H, 6.96; N, 10.02.Found: C, 59.79; H, 6.93; N, 9.76.

EXAMPLE 512,3-Dihydro-4-methyl-2-[2-(2-methyl-1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-one

To a solution of 3.5 g (0.0145 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-onein ethanol (15 ml) was added 2-methyl pyrrolidine (5.0 g, 0.063 mole).The solution was heated to reflux for 3 hours with stirring. The ethanolwas removed by rotary evaporation (water aspirator, 80° C.). Theresidual oil was partitioned between dilute aqueous sodium hydroxide (50ml) and chloroform (50 ml). The organic layer was saved and the aqueouslayer extracted with chloroform (2×30 ml). All the chloroform layerswere combined, dried over anhydrous sodium sulfate and concentrated byrotary evaporation (water aspirator, 70° C.). The residual oil was thendistilled at 200° C. and low vacuum (vacuum pump) giving 1.5 g (36.7%)of a clear oil.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₂ : C, 66.41; H, 8.01; N, 14.52.Found: C, 65.83; H, 8.06; N, 14.39.

EXAMPLE 522,3-Dihydro-4-methyl-2-[2-(1H-pyrazol-1-yl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-one

To a suspension of sodium hydride (1.2 g active, 0.05 mole) indimethylformamide (15 ml) was added dropwise a solution of pyrazole(3.10 g, 0.045 mole) in dimethylformamide (15 ml). The resultingsolution was then added to a solution of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one(9.12 g, 0.038 mole) in 30 ml of dimethylformamide. The flask was sealedand stirred overnight. Because the reaction had not yet gone tocompletion at this point, pyrazole (3.12 g, 0.045 mole) was added to thereaction solution and stirred overnight. The reaction was still notcomplete and another suspension of sodium hydride (0.5 g active, 0.021mole) and pyrazole (1.5 g, 0.022 mole) in dimethylformamide (10 ml) wasadded and the reaction stirred overnight. The reaction appeared to becomplete. Dimethylformamide was removed by rotary evaporation (80° C.,vacuum pump), and the residue taken up in chloroform (100 ml) which waswashed with dilute aqueous sodium hydroxide (1×50 ml), dried overanhydrous sodium sulfate and concentrated by rotary evaporation (70° C.,water aspirator). The material was purified by high pressure liquidchromatography, 95:5 by volume ethanol:methanol on a silica gel column.The fractions containing the desired product were concentrated by rotaryevaporation (70° C., water aspirator). Crystallization ensued uponcooling. The crystals were collected and recrystallized from ethanol.The yield was 1.5 (14.5%), m.p. 132°-134° C.

Analysis: Calculated for C₁₄ H₁₆ N₄ O₂ : C, 61.75; H, 5.92; N, 20.58.Found: C, 61.35; H, 5.89; N, 20.67.

EXAMPLE 532,3-Dihydro-2-[2-(1H-imidazol-1-yl)ethyl]-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one

To a solution of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2f][1,4]-oxazepine-5-(4H)-one,9.12 g (0.038 mole) in dimethylformamide (30 ml) was added imidazole,5.66 g (0.083 mole). The solution was heated to 130° C. for 18 hr.Dimethylformamide was removed by rotary evaporation (80° C., vacuumpump) and the residue taken up in chloroform (100 ml). The chloroformwas washed with dilute aqueous sodium hydroxide (30 ml), dried oversodium sulfate and concentrated by rotary evaporation (70° C., wateraspirator) to an oil. Crystallization was induced with ethanol. Whitecrystals, 1.5 g (14.5%) were collected, m.p. 150°-152° C.

Analysis: Calculated for C₁₄ H₁₆ N₄ O₂ : C, 61.75; H, 5.92; N, 20.58.Found: C, 61.36; H, 5.92; N, 20.60.

EXAMPLE 542-[2-(Dimethylamino)ethyl]-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate [1:1]

To 30 ml of dimethylamine collected at 0° C. was added 6 g (0.021 mole)2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one,hydrochloride. The flask was sealed tightly and stirred 70 hr at roomtemperature. The solution was then cooled to 0° C. and the stopper ofthe flask removed. Dimethylamine was allowed to evaporate. The residuewas taken up in chloroform (1×150 ml) and washed with dilute aqueoussodium hydroxide (1×50 ml). The organic layer was dried over sodiumsulfate, filtered and concentrated by rotary evaporation (70° C., wateraspirator). The residue was dissolved in hot isopropyl alcohol andtreated with oxalic acid. Upon cooling, 4.5 (61.5%) was collected, m.p.208° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₆ : C, 54.38; H, 6.56; N, 11.89.Found: C, 54.26; H, 6.61; N, 11.81.

EXAMPLE 552,3-Dihydro-4-ethyl-2-[2-(1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate[1:1]

2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-onehydrochloride, 3 g (0.01 mole) was dissolved in pyrrolidine (30 ml) andheated to 70° C. for 30 minutes with stirring. After cooling, thecontents of the reaction flask were diluted with dilute aqueous sodiumhydroxide (40 ml) and extracted with chloroform (2×30 ml). Thechloroform layer was dried over sodium sulfate, filtered andconcentrated to a viscous brown oil by rotary evaporation (70° C., wateraspirator). The oil was taken up in hot isopropyl alcohol and treatedwith oxalic acid. Upon cooling, the resulting solid was recrystallizedfrom isopropyl alcohol, giving pale brown crystals, 1.80 g (45.4%), m.p.185°-188° C.

Analysis: Calculated for C₁₈ H₂₅ N₃ O₆ : C, 56.98; H, 6.64; N, 11.07.Found: C, 56.90; H, 6.67; N, 10.90.

EXAMPLE 562,3-Dihydro-4-methyl-2-[2-(4-morpholinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-thione

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione,4.5 g (0.018 mole) was dissolved in morpholine (30 ml). The solution washeated with stirring to 50°-60° C. for 6 hr. The morpholine was thenremoved by rotary evaporation (90° C., vacuum pump). The residue wastaken up in chloroform (100 ml) and washed with dilute aqueous sodiumhydroxide (2×30 ml). The organic layer was concentrated by rotaryevaporation (60° C., water aspirator). The residue was recrystallizedfrom ethanol giving 3.26 g (60%) of light yellow crystals, m.p.152°-153° C.

Analysis: Calculated for C₁₅ H₂₁ N₃ O₂ S: C, 58.61; H, 6.89; N, 13.66.Found: C, 58.48; H, 6.92; N, 13.62.

EXAMPLE 572-[2-(Dibutylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione,4 g (0.016 mole) was suspended in di-n-butylamine (30 ml).Dimethylformamide (ca. 10 ml) was added to the stirred mixture untildissolution occurred. The solution was heated to 140° C. for 3.5 hr withstirring. Di-n-butylamine and dimethylformamide were removed by rotaryevaporation (80° C. vacuum pump). The residue was then diluted withdilute aqueous sodium hydroxide (50 ml) and extracted with chloroform(3×40 ml). Chloroform was removed by rotary evaporation (70° C., wateraspirator). The residue was dissolved in boiling isopropyl alcohol andtreated with oxalic acid. Upon cooling, the resulting oxalate salt wasfiltered and recrystallized from isopropyl alcohol to give 3.2 g (47%)of yellow crystals, m.p. 208° C.

Analysis: Calculated for C₂₁ H₃₃ N₃ O₅ S: C, 57.38; H, 7.57; N, 9.56.Found: C, 57.04; H, 7.63; N, 9.31.

EXAMPLE 582-[2-(Diethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methyl[3,2-f][1,4]oxazepine-5(4H)-thione,4 g (0.016 mole) was suspended in diethylamine (30 ml).Dimethylformamide was added to the stirred suspension until dissolutionoccurred (10 ml). The stirred solution was heated to 65° C. for 8 hr.Diethylamine was removed by rotary evaporation (70° C., wateraspirator); the remaining dimethylformamide was removed at low pressure(vacuum pump) and 90° C. The residue was taken up in chloroform (100 ml)and washed with dilute aqueous sodium hydroxide (2×30 ml). The organiclayer was concentrated by rotary evaporation (70° C., water aspirator).The residue was dissolved in boiling isopropyl alcohol and treated withoxalic acid. Upon cooling, the oxalate salt, 1.7 g (28.5%) was obtained,m.p. 142°-144° C.

Analysis: Calculated for C₁₇ H₂₅ N₃ O₅ S: C, 53.25; H, 6.57; N, 10.95.Found: C, 53.14; H, 6.60; N, 10.72.

EXAMPLE 592,3-Dihydro-4-methyl-2-[2-(1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate[1:1]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione,5 g (0.02 mole) was dissolved in 30 ml of pyrrolidine. The solution washeated to 60°-80° C. for 35 minutes with stirring. After cooling to roomtemperature, the reaction mixture was diluted with dilute aqueous sodiumhydroxide (50 ml) and extracted with chloroform (2×50 ml). The organiclayer was concentrated by rotary evaporation (70° C., water aspirator).Residual pyrrolidine was removed at 90° C. and vacuum pump. The residuewas dissolved in hot ethanol and treated with oxalic acid. Upon cooling,the oxalate salt was collected and recrystallized twice from ethanol togive 3.35 g, (45%) of product, m.p. 141° C.

Analysis: Calculated for C₁₇ H₂₃ N₂ O₅ S: C, 53.53; H, 6.08; N, 11.02.Found: C, 53.39; H, 6.11; N, 10.91.

EXAMPLE 602,3-Dihydro-2-[2-(1H-imidazol-1-yl)ethyl]-4-methylpyrido-[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate[2:3]

To a solution of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione,4.5 g (0.018 mole) in dimethylformamide (35 ml) was added imidazole(2.20 g, 0.038 mole). The resulting solution was heated to 130° C. for15 hrs. Dimethylformamide was removed by rotary evaporation (80° C.,vacuum pump), and the residue diluted with dilute aqueous sodiumhydroxide (50 ml). The aqueous solution was extracted with chloroform(1×50 ml), dried over anhydrous sodium sulfate and concentrated byrotary evaporation (water aspirator, 70° C.). The resulting oil wastreated with oxalic acid in ethanol. Four grams (54%) of pale yellowcrystals were collected and recrystallized again with ethanol, m.p.163°-167° C.

Analysis: Calculated for C₁₇ H₁₈ O₇ N₄ S: C, 48.22; H, 4.52; N, 13.23.Found: C, 48.04; H, 4.62; N, 13.18.

EXAMPLE 61 2-[2-(Dimethylamino)ethyl]-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-thione

2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-thionehydrochloride, 5.00 g (0.016 mole) was added to 20 ml of anhydrousdimethylamine. The reaction flask was sealed tightly and stirred at roomtemperature for 6 days. The flask was opened after cooling to 0° C. anddimethylamine allowed to evaporate at room temperature. The residue wastaken up in chloroform (100 ml) and washed with dilute aqueous sodiumhydroxide (1×30 ml). The chloroform layer was dried over sodium sulfate,filtered and concentrated by rotary evaporation. The residual oil wasdissolved in hot cyclohexane. Upon cooling, 1.76 g (39.4%) of lightyellow crystals were collected, m.p. 73° C.

Analysis: Calculated for C₁₄ H₂₁ N₃ OS: C, 60.18; H, 7.58; N, 15.03.Found: C, 60.32; H, 7.70; N, 15.13.

EXAMPLE 622,3-Dihydro-4-methyl-2-[2-[methyl(phenylmethyl)amino]ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate [1:1]

To a solution of 4 g (0.0155 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionein 70 ml of chloroform was added 10.0 g (0.086 mole) ofbenzylmethylamine. The solution was stirred at reflux for 24 hr. Thereaction solution was washed with water (2×50 ml) and concentrated byrotary evaporation (˜70° C., water aspirator). The residue was distilledon a molecular still at 165° C./0.1 mm. The residue was treated withoxalic acid in hot isopropyl alcohol. Upon cooling, two crops ofcrystals were collected. The purity of each crop was checked. The twocrops were combined and recrystallized together in hot isopropylalcohol. Upon cooling, 3.69 g (55%) of pale yellow crystals, m.p.163°-166° C. were collected.

Analysis: Calculated for C₂₁ H₂₅ N₃ O₅ S: C, 58.45; H, 5.84; N, 9.74.Found: C, 58.24; H, 5.92; N, 9.61.

EXAMPLE 632,3-Dihydro-2-[2-(methylamino)ethyl)-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate [1:1.5]

2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione,4.0 g (0.016 mole) was suspended in a 30% solution of methylamine in 70ml of ethanol and allowed to stir for 56 hr at room temperature. Becauseof incomplete reaction, the reaction solution was heated slowly over a 2hr period to 55° C. and stirred at that temperature for 24 hr.Methylamine was removed by water aspiration for 1.5 hr. The resultingsolution was concentrated by rotary evaporation (70° C., wateraspirator). The residual oil was taken up in chloroform (150 ml) andwashed with 2M aqueous potassium hydroxide (2×50 ml). The chloroformlayer was dried over sodium sulfate and concentrated by rotaryevaporation (70° C., water aspirator). The residue was dissolved in hotethanol and treated with oxalic acid. Upon cooling, 2.0 g (37.5%) ofyellow crystals were collected, m.p. 137°-138° C.

Analysis: Calculated for C₁₅ H₂₀ N₃ O₇ S: C, 46.63; H, 5.22; N, 10.67.Found: C, 46.47; H, 5.35; N, 10.85.

EXAMPLE 647-Chloro-2,3-dihydro-4-methyl-2-[2-[1-pyrrolidino)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-onefumarate [1:2.5]

7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one (2.5 g, 0.009 mole) was dissolved in 50ml pyrrolidine and the solution was heated to 80° C. for 1 hr. Thepyrrolidine was removed by rotary evaporation (80° C., water aspirator)and the residue dissolved in 100 ml of chloroform. The organic layer waswashed with water (2×50 ml), dried over sodium sulfate and concentratedby rotary evaporation (˜80° C., water aspirator). The residue wastreated with fumaric acid and allowed to stand overnight. The resultingcrystals were collected, 1.25 g (23.2%), m.p. 164°-166° C.

Analysis: Calculated for C₂₅ H₃₀ N₃ O₁₂ Cl: C, 50.05; H, 5.04; N, 7.00.Found: C, 50.22; H, 5.14; N, 7.02.

EXAMPLE 657-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate [1:1]

A 2.8 g (0.01 mole) sample of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onewas added to 25 ml of dimethylamine and stirred for 96 hr in a sealedflask. The excess amine was allowed to evaporate and the residue waspartitioned between chloroform and dilute sodium hydroxide. Thechloroform was dried over sodium sulfate and concentrated. The residuewas treated with 0.7 g of oxalic acid in isopropyl alcohol. Theresulting crystals were recrystallized from the same solvent. Yield was1.5 g of oxalate salt (40%), m.p. 150°-156° C.

Analysis: Calculated for C₁₅ H₂₀ N₃ O₆ Cl: C, 48.20; H, 5.39; N, 11.24.Found: C, 48.09; H, 5.47 N, 11.12.

EXAMPLE 664-Cyclohexyl-2-[(dimethylamino)methyl]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate

Utilizing the procedure of Example 10,2-(chloromethyl-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one(Intermediate 35) is reacted with 40% aqueous dimethylamine and reactedwith oxalic acid in isopropyl alcohol.

EXAMPLE 672-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate [1:1.5] hemihydrate

A solution containing 94.2 g (0.6 mole) of 2 chloronicotinic acid and100 g (0.54 mole) of 1-benzyl-3-pyrrolidinol in 800 ml of drytetrahydrofuran was added at a rapid drop to a stirred suspension of 52g (1.3 mole) of 60% sodium hydride/mineral oil in 500 ml of drytetrahydrofuran at reflux temperature (addition time was about 1 hr).The mixture was heated to reflux for an additional 1.5 hr and thencooled to room temperature. Approximately 1 liter of ethyl acetate wasadded and filtration attempted unsuccessfully. The mixture was allowedto stand overnight at room temperature and then was concentrated on therotary evaporator at 100° C. and 50 mm pressure. The residue wasdissolved in 1 liter of chloroform and the pH of the solution wasadjusted to 6.15 with hydrogen chloride gas. To the solution was added,with stirring, 383 g (1.0 mole) of triphenylphosphine and 383 g (2.48mole) of carbon tetrachloride. The mixture was refluxed for 1 hr and 50ml of ethanol was added. The solution was cooled to room temperature andextracted three times with 400 ml portions of dilute hydrochloric acid.The chloroform layer was extracted with dilute sodium hydroxide, driedover sodium sulfate and concentrated. The mass spectra indicated thepresence of2-(2-chloroethyl)-2,3-dihydro-4-(phenylmethyl)pyrido[3,2-f][1,4]oxazepin-5(4H)-one(mass 316), triphenylphosphine (mass 262) and triphenylphosphine oxide(mass 278). One-third of the residue was chromatographed on a highpressure liquid chromatopraph in an unsuccessful attempt to purify thecompound. The other 2/3 of the residue was dissolved in 30 ml ofchloroform and added to a solution of 30 g of dimethyl amine in ethanol.The solution was heated to reflux for 4 hr and concentrated on therotary evaporator. The residue was partitioned between chloroform and 1Nhydrochloric acid. The acid layer was made basic with sodium hydroxideand extracted with chloroform. The chloroform layer was dried oversodium sulfate and concentrated. The residue (10 g) was treated with anequivalent amount of oxalic acid in a mixture of isopropylalcohol-ethanol-isopropyl ether. The resulting crystals in the amount of9 g (5%) were recrystallized from the same solvent mixture, m.p. 95°-98°C.

Analysis: Calculated for C₄₄ H₅₄ N₆ O₁₇ : C, 56.28; H, 5.79; N, 8.95.Found: C, 56.61; H, 5.76; N, 8.77.

EXAMPLE 68-A2-[2-(Dimethylamino)ethyl]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one

A solution of 3.0 g (0.006 mole) of 2-[2-(dimethylaminoethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate [1:1.5]-hemihydrate in about 50 ml of water was made basic withdilute aqueous sodium hydroxide solution and then extracted with three50 ml portions of benzene. The combined benzene extract was dried overanhydrous sodium sulfate and concentrated on the rotary evaporator(steam bath/50 mm). The residue was dried further by azeotroping 2 timeswith about 50 ml of dry benzene, evaporating to dryness each time. Thefinal residue was dissolved in 40 ml of liquid ammonia and small spheresof sodium were added with stirring to the solution until a blue colorpersisted for 20 minutes. (Addition time was about 1 hr). Three grams ofammonium chloride was added slowly and the ammonia was allowed toevaporate. The residue was suspended in chloroform and the mixture wasfiltered. The filtrate was concentrated and the residue chromatographedon preparative high pressure liquid chromatograph using a silica gelcolumn and eluting with 75% ethyl acetate/25% dimethylformamide. Theyield of product was 0.1 g (7%). The chemical ionization massspectrophotometer gave a peak at 236 corresponding to a molecular weightof 235. The ¹ H NMR spectrum of the subject compound was obtained inCDCl₃ containing 1% tetramethylsilane (TMS) and is consistent with theproposed structure and dimethylformamide (DMF) and mineral oil as minorimpurities. The chemical shifts, multiplicities, and assignments aregiven below:

    ______________________________________                                         ##STR50##                                                                    Chemical Shifts (multiplicities)                                                                Assignments                                                 ______________________________________                                        8.45 (multiplet)  H(8) and H(6)                                               8.00 (singlet)    CH (DMF)                                                    7.85 (broad singlet)                                                                            NH                                                          7.20 (doublet of doublets)                                                                      H(7)                                                        4.65 (pentet)     H(2)                                                        4.05 (broad singlet)                                                                            unknown impurity                                            3.50 (triplet)    H.sub.2 (3)                                                 2.95 (singlet)    CH.sub.3 (DMF)                                              2.90 (singlet)    CH.sub.3 (DMF)                                              2.60 (triplet)    H.sub.2α to amino nitrogen                            2.25 (singlet)    N(CH.sub.3).sub.2                                           2.05 (multiplet)  H.sub.2β to amino nitrogen                             0.7-1.7 (multiplet)                                                                             mineral oil                                                 ______________________________________                                    

EXAMPLE 68-B (REFER TO CHART VIII)2-[2-(Dimethylamino)ethyl)-2,3-dihydropyrido[3,2-f]-1,4-oxazepin-5(4H)-onefumarate [1:1]

An 8 g (0.026 mole) sample of2-chloro-N-[4-(dimethylamino)-2-hydroxybutyl]-3-pyridinecarboxamidemonohydrochloride was partitioned between chloroform and dilute sodiumhydroxide. The chloroform was dried over anhydrous sodium sulfate andconcentrated. The residue was dissolved in 80 ml of dry benzene whichwas removed on the rotary evaporator (100° C./30 min). The residue in 20ml of dry tetrahydrofuran was added slowly to a stirred suspension of8.3 g (0.052 mole) of potassium hydride/mineral oil in 80 ml of drytetrahydrofuran. The mixture was stirred at reflux for 4 hr, cooled andtreated with 10 ml of isopropyl alcohol. The solution was partitionedbetween isopropyl ether and dilute hydrochloric acid. The acid layer wasmade basic with sodium hydroxide and extracted 4 times with chloroform.The chloroform was concentrated and the residue was chromatographed onHPLC (silica; 90% ethanol-10% triethylamine. The desired fractions wereconcentrated and the residue (1.3 g) treated with 0.7 g of fumaric acidin 25 ml of isopropyl alcohol. The resulting crystals weighed 1.2 g(13%) and melted at 160°-164° C.

Analysis: Calculated for C₁₆ H₂₁ N₃ O₆ : C, 54.69; H, 6.02; N, 11.96.Found: C, 54.29; H, 6.02; N, 11.54.

EXAMPLE 692-[3-(Dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onefumarate [1:1.5] hemihydrate

To 5.0 g (0.21 mole) of2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onewas added, while cooling in a water bath, an 88% aqueous solution offormic acid, 20 g (0.38 mole). To the resulting solution was added asolution of 37% aqueous formaldehyde (inhibited with 13% methanol), 10.7g (0.13 mole). The resulting solution was heated on a steam bath for 5.5hr. The mixture was cooled and 100 ml of dilute aqueous hydrochloricacid was added. The solution was evaporated to dryness and the residuewas dissolved in 50 ml of water. The solution was neutralized withdilute aqueous potassium hydroxide and extracted with four 50 mlportions of chloroform. The combined chloroform extracts was dried oversodium sulfate and concentrated by rotary evaporation. The residue wasreacted with fumaric acid in hot isopropyl alcohol. The collectedproduct, 3.0 g (31.8%) was recrystallized twice from isopropyl alcohol,m.p. 108°-110° C.

Analysis: Calculated for C₄₀ H₅₆ N₆ O₁₇ : C, 53.81; H, 6.32; N, 9.41.Found: C, 53.69; H, 6.33; N, 9.41.

EXAMPLE 702-[3-(Dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thioneoxalate [1:2]

To a solution of 11.0 g (0.042 mole) of2-[3-(dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onein 125 ml of pyridine was added 9.25 g (0.042 mole) of phosphoruspentasulfide. The mixture was heated to reflux for 3.5 hr whilestirring. After cooling to room temperature, the reaction solution wasadded to an equal volume of 2 molar potassium hydroxide. The mixture wasextracted with 800 ml of methylene chloride in several portions. Theorganic phase was washed with three 100 ml portions of dilute potassiumhydroxide, dried over sodium sulfate, filtered and concentrated byrotary evaporator (water-aspirator, 70° C.). The residual oil wassubjected to reduced pressure of the vacuum pump for 2 hr at 90° C. andthen cooled and reacted with oxalic acid in isopropyl alcohol. Twocrops, 4.5 and 3.1 g were collected, combined and recrystallized fromisopropyl alcohol to give 6.5 g (34%) of yellow crystals, m.p. 136°-138°C.

Analysis: Calculated for C₁₈ H₂₅ N₃ O₉ S: C, 47.05; H, 5.42 N, 9.16.Found: C, 46.76; H, 5.75; N, 9.04.

EXAMPLE 717-Chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate [1:1] hemihydrate, hemiisopropyl alcoholate

To 55 ml of a methanolic solution containing 57% by volume dimethylaminewas added 2.50 g (0.009 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione.The reaction vessel was sealed and allowed to stand for 16 hr.Thin-layer chromatography indicated the reaction was about 60% complete.The solution was heated gradually to 45° C. (heating time about 5 hr).Methanol and unreacted dimethylamine were removed by rotary evaporator(water aspirator, 60° C.). The residue was taken up in 100 ml ofchloroform and the solution was washed with two 40 ml portions of water.The organic layer was dried over sodium sulfate, filtered andconcentrated by rotary evaporator. The residue was reacted with fumaricacid in isopropyl alcohol. The resulting crystals, 1.43 g (36.5%) wererecrystallized from isopropyl alcohol and dried thoroughly in a dryingpistol, m.p. 98°-104° C.

Analysis: Calculated for C₃₇ H₅₄ N₆ O₁₂ Cl₂ S₂ : C, 48.84; H, 5.98; N,9.23. Found: C, 48.82; H, 5.80; N, 9.37.

EXAMPLE 722,3-Dihydro-4-methyl-2-[2-(methylamino)ethyl]pyrido-[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To 90 ml of a solution of 30% monomethylamine in ethanol was added 11.0g (0.04 mole) of2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onehydrochloride. The solution was heated gradually over a period of 2 hrto 55° C. and held at that temperature overnight.

Monomethylamine and ethanol were removed by rotary evaporation (wateraspirator, 70° C.) and the residue was taken up in 100 ml of chloroform.The organic layer was washed with dilute aqueous sodium hydroxide (2×30ml), dried over anhydrous sodium sulfate, filtered, and concentrated byrotary evaporation (70° C., water aspirator). The 9.0 g of crude oil wastreated with oxalic acid in isopropyl alcohol. The resulting crystalsweighed 8.77 g (67.8%), m.p. 148°-50° C.

Analysis: Calculated for C₁₄ H₁₉ N₃ O₆ : C, 51.69; H, 5.89; N, 12.92.Found: C, 51.88; H, 5.97; N, 12.96.

EXAMPLE 732-(2-Aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one,fumarate [1:1]

To a suspension of 17.0 g (0.048 mole) of2,3-dihydro-2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-4-methylpyrido[3,2-f]oxazepin-5(4H)-onein 100 ml of absolute ethanol was added 3.0 g (0.051 mole) of 85%hydrazine hydrate in water and the mixture heated to reflux withstirring. In 15 minutes the reaction mixture became clear. After 40 mina copious precipitate of presumably phthaly hydrazide had formed.Another 100 ml of absolute ethanol was added to ensure good mixing.After 2 hr at reflux, the cooled mixture was filtered. The filtrate wasconcentrated on the rotary evaporator (water aspirator, 80° C.) and theresidue taken up in 75 ml of chloroform. The organic layer was washedwith dilute aqueous sodium hydroxide (2×3 ml), dried over anhydroussodium sulfate, filtered, and the filtrate concentrated by rotaryevaporation (water aspirator, 75° C.). The residue was treated withfumaric acid in isopropyl alcohol and yielded 7.0 g (43%) of pale whitecrystals, m.p. 196°-197° C.

Analysis: Calculated for C₁₅ H₁₉ N₃ O₆ : C, 53.41; H, 5.68; N, 12.46.Found: C, 53.63; H, 5.78 N, 12.33.

EXAMPLE 742-(2-Aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-thione,fumarate [2:1]

To a suspension of 12.15 (0.033 mole) of2-[2-(2,3-dihydro-5(4H)-thioxopyrido[3,2-f][1,4]oxazepin-2-yl)ethyl]-1H-isoindole-1,3(2H)dionein 150 ml of absolute ethanol was added 2.08 g (0.035 mole) of an 85%solution of hydrazine hydrate in water. The mixture was heated to refluxfor 2 hrs. After cooling, solid phthalylhydrazide was filtered off.Ethanol was removed by rotary evaporation (85° C., water aspirator) andthe residue partitioned between 180 ml chloroform and 50 ml diluteaqueous sodium hydroxide. The organic layer was washed further withdilute aqueous sodium hydroxide (3×30 ml), dried over anhydrous sodiumsulfate, filtered and concentrated by rotary evaporation (wateraspirator, 70° C.). The crude oil was treated with fumaric acid inisopropyl alcohol which yielded 6.70 g (68.7%) of pale yellow crystals,m.p. 208°-09° C.

Analysis: Calculated for C₁₃ H₁₇ N₃ O₃ S: C, 52.87; H, 5.80; N, 14.23.Found: C, 52.72; H, 5.81; N, 14.16.

EXAMPLE 752,3-Dihydro-4-methyl-2[2-[(1-methylethyl)amino]ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-one,fumarate [1:2]

To a solution of 2.52 g (0.011 mole) of2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onein 50 ml dry methanol was added methanolic hydrogen chloride until pH 6was reached. To this solution was added 3.29 g (0.057 mole) of acetone,1.79 g (0.029 mole) of sodium cyanoborohydride and 5 g 3 A molecularsieves. The pH was checked and readjusted to pH 7-8 with methanolichydrogen chloride and stirred 24 hr at room temperature. The reactionmixture was filtered, and concentrated by rotary evaporation (70° C.,water aspirator). The residue was taken up in 100 ml of chloroform,washed with dilute aqueous sodium hydroxide, dried over anhydrous sodiumsulfate, filtered, and concentrated by rotary evaporation (wateraspirator, 70° C.). The residue was treated with fumaric acid inisopropyl alcohol which gave 1.58 g (29%) of white crystals, m.p.152°-153° C.

Analysis: Calculated for C₂₂ H₂₉ N₃ O₁₀ : C, 53.33; H, 5.89; N, 8.48.Found: C, 53.43; H, 5.94; N, 8.54.

EXAMPLE 762-[2-[Bis(phenylmethyl)amino]ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione,fumarate [1:1]

To a solution of 3.16 g (0.013 mole) of2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-e][1,4]oxazepine-5(4H)thione in ˜25 ml dry methanol was added methanolic hydrogen chloride topH 5-6, followed by ˜2-3 g 3 A molecular sieves, 6.89 g (0.065 mole)benzaldehyde and 2.04 g (0.0325 g)sodium cyanoborohydride. The pH wasagain adjusted to pH 7 with methanolic hydrogen chloride. After 6 hr ofstirring at room temperature, TLC (eluting with 6% triethylamine inmethanol) showed what appeared to be exclusively monoalkylated productwith very little starting material. To the reaction mixture was thenadded 1.0 g (0.009 mole) of benzaldehyde and the mixture stirredovernight at room temperature. The reaction mixture was filtered andconcentrated by rotary evaporation (70° C., water aspirator). Theresidue was taken up in 100 ml of chloroform and washed with 2×30 mldilute aqueous sodium hydroxide. The chloroform was removed by rotaryevaporation (70° C., water aspirator). The residue was dissolved in 100ml dilute hydrochloric acid which was subsequently washed with 2×30 mlethyl acetate, made basic with dilute aqueous sodium hydroxide,extracted with 4×30 ml chloroform. The chloroform was dried overanhydrous sodium sulfate, filtered anc concentrated by rotaryevaporation (70° C., water aspirator. The residue showed both the mono-and di-alkylated product by TLC (6% triethylamine/94 methanol) and NMR.

To a solution of the 3.0 g crude material dissolved in 30 ml drymethanol was added methanolic hydrogen chloride to pH 4-5, 10.0 g(10.094 mole) of benzaldehyde and 2.00 g (0.0319 mole) of sodiumcyanoborohydride. The pH was neutral. To the reaction mixture was added˜1 g of 3 A molecular sieves. The reaction mixture was stirred for 6days at room temperature.

The methanol was removed by rotary evaporation (70° C., water aspirator)after filtration. The residue was dissolved in ˜100 ml chloroform andwashed with 2×50 ml dilute aqueous sodium hydroxide. The chloroform wasremoved by rotary evaporation (70°, water aspirator) and the residuedissolved in 100 ml of dilute aqueous hydrochloric acid. The aqueouslayer was washed with 2×50 ml of ethyl acetate (the ethyl acetate wasextracted with 2×30 ml of dilute hydrochloric acid and all acid layerscombined; this was done because the product appeared to be somewhatsoluble in ethyl acetate). The hydrochloric acid layer was made basicwith concentrated sodium hydroxide solution and extracted with 2×50 mlof chloroform. The chloroform layer was dried over anhydrous sodiumsulfate, filtered and concentrated by rotary evaporation (70° C., wateraspirator. The 3.0 g of crude product obtained was dissolved in hotisopropyl alcohol) and treated with fumaric acid. The resultingcrystals, 1.40 g (20.2%), melted at 123°-126° C. with slight shrinkageoccurring at 118° C.

Analysis: Calculated for C₂₉ H₃₁ N₃ O₅ S: C, 65.27; H, 5.86; N, 7.87.Found: C, 65.11; H, 5.87; N, 8.05.

EXAMPLE 772,3-Dihydro-4-methyl-2-[2-(4-methyl-1-piperazinyl)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-onefumarate[1:2]monohydrate

To a solution of 10.45 g (0.043 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-onein 80 ml of absolute ethanol was added 10.84 g (0.1084 mole) of N-methylpiperazine and the resulting solution heated to reflux for 4 hr. At thattime, because ˜25% starting material was present by mass spec, anadditional 5.0 g (0.05 mole) of N-methyl piperazine was added andheating to reflux was continued for 2 hr. Ethanol was removed by rotaryevaporation (70°, water aspirator) and the residue diluted with 150 mlof water. The water was extracted with 4×50 ml of chloroform and theorganic layer was washed with 2×50 ml of water, dried over anhydroussodium sulfate, filtered and concentrated by rotary evaporation (70° C.,water aspirator). The residue was concentrated (vacuum pump/95°-100° C.)for 3.5 hr. Treatment of the residue with fumaric acid in isopropylalcohol yielded 8.45 g (35.4%) of pale white crystals, m.p. 162°-167° C.

Analysis: Calculated for C₂₄ H₃₄ N₄ O₁₁ : C, 51.98; H, 6.17; N, 10.10.Found: C, 52.03; H, 6.00; N, 10.17.

EXAMPLE 782,3-Dihydro-4-methyl-2-[2-(4-methyl-1-piperazinyl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate[1:2]hemihydrate

To 8.0 g (0.031 mole of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5-(4H)-thionein 80 ml of absolute ethanol was added 9.30 g (0.093 mole) of N-methylpiperazine. The mixture was heated to reflux for 2 hr and an additional5.0 g (0.5 mole) N-methyl piperazine was added. Reflux was continued foran additional 5 hr.

Ethanol was removed by rotary evaporation (90° C., water aspirator).Residual N-methyl piperazine was removed at 90° C. with vacuum pump for2 hr. The residue was taken up in 150 ml of chloroform and washed with2×50 ml of water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated by rotary evaporation (90° C., wateraspirator). The residue was concentrated further with a vacuum pump at90° C. The 10.0 g of crude material was treated with fumaric acid inisopropyl alcohol which yielded 10.0 g (57.4%) of light yellow crystals,m.p. 184°-185° C.

Analysis: Calculated for C₂₄ H₃₃ N₄ O₉.5 S: C, 51.32; H, 5.92; N, 9.98.Found: C, 51.56; H, 5.89; N, 9.86.

EXAMPLE 792-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onedihydrochloride hemihydrate

Ten grams (0.036 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-onehydrochloride were partitioned between dilute sodium hydroxide andchloroform. The chloroform was dried over sodium sulfate andconcentrated on the rotary evaporator. The residue was dissolved in 50ml of ethanol and 10.3 g (0.036 mole) of4-[bis(4-fluorophenyl)-methyl]piperidine was added. The solution washeated to reflux for 18 hr and concentrated on the rotary evaporator.The residue was partitioned between dilute sodium hydroxide andchloroform. The chloroform was dried over anhydrous sodium sulfate andconcentrated. The residue was chromatographed on a Waters 500 HPlC(silica/92% ethyl acetate-8% triethylamine). After concentration of thedesired product, the residue was dissolved in isopropyl alcohol andtreated with ethereal hydrogen chloride. The resulting crystals weighed3 g (14%) and melted at 160°-180° C.

Analysis: Calculated for C₅₈ H₆₈ N₆ O₅ Cl₄ F₄ : C, 60.73; H, 5.98 N,7.33. Found: C, 60.60; H, 6.04 N, 7.12.

EXAMPLE 802-[2-(4,5-Dihydro-1H-imidazol-2-yl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate[1:1]

Into a cooled (water bath) solution of 10 g (0.043 mole) of2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,49oxazepine-2-propane-nitrile in 50 ml of ethylenediamine was bubbledhydrogen sulfide gas for 10 min. The reaction flask was tightlystoppered and left standing at room temperature for 5 days. The reactionsolution (now partially solidified) was diluted with 100 ml of dilutesodium hydroxide and extracted with 5×30 ml of chloroform. The organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated by rotary evaporation (70° C., water aspirator). The entireresidue was dissolved in 50 ml of ethylenediamine and saturated withhydrogen sulfide for 10 minutes while cooling in a water bath. The flaskwas tightly stoppered and left standing at room temperature for 5 days.The contents of the reaction flask were diluted with 200 ml of 2Naqueous potassium hydroxide and extracted with 3×125 ml of chloroform.The organic extracts were washed with 3×50 ml 2N aqueous potassiumhydroxide and extracted into 3×50 ml of dilute aqueous hydrochloricacid. The acid extracts were basified with concentrated sodium hydroxideand extracted into 3×40 ml of chlofoform. The organic extracts weredried over sodium sulfate, filtered and concentrated by rotaryevaporation. The syrupy residue was treated with oxalic acid inisopropyl alcohol to give 3.5 g (22%) of white crystals. Onerecrystallization from isopropyl alcohol afforded an analytical sample,m.p. 198° C. with decomposition.

Analysis: Calculated for C₁₈ H₂₁ N₄ O₆ : C, 52.74; H, 5.53; N, 15.38.Found: C, 52.76; H, 5.58; N, 15.51.

EXAMPLE 812,3-Dihydro-4-methyl-2-[2-(methylphenylamino)ethyl]pyrido[3,2-f][1,4]oxazepin-5(4H)-thione

To a suspension of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionein 100 ml of toluene was added 11.49 g (0.11 mole) N-methylaniline andthe mixture heated to reflux with stirring for 2 days (after approx. 6hr, 23.0 g (0.22 mole) additional N-methylaniline was added). Toluenewas removed by rotary evaporation (90° C., water aspirator). TheN-methylaniline was removed also by rotary evaporation (90° C., vacuumpump). The residue was taken up in 100 ml of chloroform and washed with3×30 ml dilute aqueous sodium hydroxide. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated by rotaryevaporation (80° C., water aspirator). More N-methylaniline was removedwith the vacuum pump at 90° C. for several hours. To the residue wasadded 150 ml of ethyl acetate at which point some product crystallizedout. However, since much remained in solution, preparative HPLC on asilica gel column eluting with 60% hexane/40% ethyl acetate waseffected. After concentrating the flasks containing the product,crystallization was effected induced by seeding. The chromatographedproduct was recrystallized from ethyl acetate/isopropyl alcohol andamounted to 1.1 g m.p. 164°-5° C. Approximately 2 g additional wascollected by recrystallization of crude product, m.p. 163°-4° C. Thecombined yield was 3.1 g (26%).

Analysis: Calculated for C₁₈ H₂₁ N₃ OS: C, 66.03; H, 6.46; N, 12.83.Found: C, 65.72; H, 6.51 N, 13.13.

EXAMPLE 822-(3-Aminopropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate[1:1]

A sample of 15.0 g (0.064 mole) of2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onewas dissolved in 50 ml methylene chloride and to it was added 15.24 g(0.07 mole) of di-tertbutyl dicarbonate. The solution was stirred for 30minutes at room temperature. The protected amine was purified by HPLC ona silica gel column, eluting with ethyl acetate. Approximately 15 g(0.045 mole 70.3%) of the protected amine was collected as an oil. To asolution of 13.5 g (0.04 mole) of this oil in dry toluene was added 8.16g (0.02 mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. Thereaction mixture was heated to 80° C. for 2 hr. An additional amount(2.0 g, 0.005 mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide wasadded and heating continued for 1 hr. Another 4.0 g (0.01 mole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide wasadded and the heating continued for 5 hr. After cooling, the toluene wasdecanted off, washed with 5×30 ml dilute aqueous sodium hydroxide, driedover sodium sulfate, filtered and concentrated by rotary evaporation.Isopropyl alcohol was added to the residue, resulting in precipitationof an impurity (possibly spent Lawesson's Reagent). Isopropyl alcoholwas removed by rotary evaporation and the residue purified by HPLC on asilica gel column, eluting with 1% methanol/99% chloroform.Approximately 6 g (0.017 mole, 42.6%) of material was collected andtreated with 100 ml of a solution of trifluoro aceticacid/anisole/methylene chloride, 40/10/50, v/v/v for 30 minutes. Thesolvent blend was removed by rotary evaporation (70° C., wateraspirator) and the residue taken up in 150 ml of methylene chloride.This layer was washed with 3×40 ml dilute aqueous sodium hydroxide,dried over anhydrous sodium sulfate, filtered and concentrated by rotaryevaporation. The residue was treated with fumaric acid in isopropylalcohol, which yielded 4.0 g (0.011 mole, 64%) of the salt.Recrystallization from isopropyl alcohol afforded an analytical sample,m.p. 164°-166° C.

Analysis: Calculated for C₁₆ H₂₁ N₂ O₅ : C, 52.30; H, 5.76; N, 11.43.Found: C, 52.43; H, 5.83; N, 11.51.

EXAMPLE 832-[2-(Dimethylamino)ethyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-5(4H)-thionedihydrochloride monohydrate

To 5 g (0.021 mole of2-[2-(dimethylamino)ethyl)-2,3-dihydropyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 50 ml of pyridine was added 5.1 g (0.046 mole) of phosphoruspentasulfide. An exothermic reaction insued. When the temperaturedropped, the mixture was heated to 70° C. for 3.5 hr and allowed tocool. The mixture was partitioned between dilute sodium hydroxide andchloroform while cooling by addition of ice. The aqueous layer wasextracted 3 more times with chloroform. The combined chlofoform extractswere dried over anhydrous sodium sulfate and concentrated. The residuewas dissolved in 40 ml of ethanol and made acidic with ethereal hydrogenchloride. The resulting crystals were recrystallized from 95% ethanol.Yield was 1.4 g (19%), m.p. 172°-175° C.

Analysis: Calculated for C₁₂ H₂₁ N₃ SO₂ Cl₂ : C, 42.10; H, 6.18 N,12.28. Found: C, 42.66; H, 5.74; N, 12.34.

EXAMPLE 842-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-thioneoxalate hydrate[1:1:1]

A solution of 4 g (0.016 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneand 4.5 g (0.016 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine in 100ml of ethanol was refluxed for 48 hr. One gram of K₂ CO₃ was added andthis mixture stirred at reflux for 144 hr. The mixture was concentratedand the residue partitioned between chloroform and dilute sodiumhydroxide. The chloroform was dried over anhydrous sodium sulfate andconcentrated. The residue was chromatographed on a Waters®500 HPLC usinga silica column and eluting with absolute ethanol. The material withmass 507 was collected and concentrated. The residue (6 g) was reactedwith 1.2 g of oxalic acid in ethanol. Yield was 5 g, m.p. 125°-138° C.

Analysis: Calculated for C₃₁ H₃₅ N₃ O₆ SF₂ : C, 60.47; H, 5.72; N, 6.82.Found: C, 60.62; H, 5.60; N, 6.68.

EXAMPLE 852,3-Dihydro-4-methyl-2-[2-(1H-pyrazol-1-yl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thione

To a suspension of 2.16 g (0.054 mole) of sodium hydride in 20 ml ofdimethylformamide was added dropwise a solution of 2.92 g (0.043 mole)of pyrazole in 10 ml of dimethylformamide. There was a slight exothermat this point with some evolution of hydrogen gas. The resultingsolution was then added dropwise to a solution of 10.0 g (0.039 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 30 ml of dimethylformamide. The reaction flask was sealed and stirredovernight at room temperature.

The solvent dimethylformamide was removed by rotary evaporation (90° C.;30 mm). The residue was taken up in 200 ml of chloroform which wassubsequently washed with 2×50 ml of water followed by 50 ml dil. aqueoussodium hydroxide. The organic layer was then dried over sodium sulfate,filtered and concentrated by rotary evaporation (70° C.; 30 mm).Isopropyl alcohol was added to the residue and crystallization ensuedafter cooling. The crude crystals (4.5 g) were recrystallized fromisopropyl alcohol giving 3.45 g (31%) of yellow crystals, m.p. 119°-121°C.

Analysis: Calculated for C₁₄ H₁₆ N₄ OS: C, 58.31; H, 5.59; N, 19.43.Found: C, 58.01; H, 5.59; N, 19.37.

EXAMPLE 862-[2-(Dimethylamino)-1-methylethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate[1:1]

To 4.5 g (0.018 mole of2-(2-chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onewas added 20 ml of methanol and 40 ml of dimethylamine. The reactionflask was tightly sealed and left standing at room temperature for 72hr. The flask was opened after cooling and the methanol anddimethylamine evaporated. Another 15 ml of methanol and 40 ml ofdimethylamine were added, the flask sealed tightly and left standing atroom temperature for 7 days. The methanol and dimethylamine wereevaporated and the residue taken up in 100 ml of chloroform. Thechloroform layer was washed with 2×50 ml dil sodium hydroxide and 50 mlof water, dried over anhydrous sodium sulfate, filtered and concentratedby rotary evaporation. The crude material which was collected wastreated with oxalic acid in isopropyl alcohol which afforded 3.5 g (55%)white crytals, m.p. 204°-05° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₆ : C, 54.38; H, 6.56; N, 11.89.Found: C, 54.32; H, 6.61; N, 11.86.

EXAMPLE 872,3-Dihydro-2-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate[2:3]

Into a suspension of2,3,4,5-tetrahydro-4-methyl-5-thioxopyrido[3,2-f][1,4]-oxazepine-2-propanenitrilein 30 ml of ethylene diamine was bubbled hydrogen sulfide gas for 15 minwhile cooling in a water bath. The flask was then sealed and stirred atroom temperature for 5 days. Mass spectra showed much starting material.An additional 15 ml of methylene diamine was added and the mixturesaturated again with hydrogen sulfide. The flask was resealed and leftstanding for 8 days. The reaction mixture was diluted with 100 ml dilaqueous sodium hydroxide and extracted into 3×60 ml of chloroform. Thechloroform extracts were combined and washed with 50 ml of water. Somecrystallization occurred in the separatory funnel but completecrystallization could not be effected. The organic layer wasconcentrated by rotary evaporation and the residue treated with oxalicacid in isopropyl alcohol. The crude crystals, 7.0 g, (55%) wererecrystallized from methanol/ethanol yielding an analytical sample, m.p.198°-200° C.

Analysis: Calculated for C₁₇ H₂₁ N₄ O₇ S: C, 47.99; H, 4.97; N, 13.16.Found: C, 47.63; H, 5.09; N, 13.04.

EXAMPLE 882-[2-(Dimethylamino)ethyl]-2,3-dihydro-2,4-dimethylpyrido[3,2-f][1,4]oxazepin-5(4H)-onedihydrochloride

To 4.5 g (0.015 mole) of2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onehydrochloride in 15 ml of methanol was added 40 ml of dimethylamine. Theflask was sealed tightly and left standing at room temperature for 8days. The methanol and dimethylamine were removed by rotary evaporation(70° C.; 30 mm). The residue was taken up in 150 ml of chloroform,washed with 2×50 ml dil aqueous sodium hydroxide, dried over anhydroussodium sulfate, filtered and concentrated by rotary evaporation (70° C.;30 mm). The syrupy residue was treated with hydrogen chloride inisopropyl alcohol, which afforded 3.5 g (67%) of white crystals, m.p.188°-90° C.

Analysis: Calculated for C₁₄ H₂₃ N₃ O₂ Cl₂ : C, 50.01; H, 6.89; N,12.50. Found: C, 50.00; H, 6.98 N, 12.49.

EXAMPLE 892-[2-(Dimethylamino)ethyl]-2,3-dihydro-2,4-dimethylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionemonohydrochloride

To a suspension of 4.5 g (0.017 mole) of2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 20 ml of methanol, cooled in an ice bath, was added 40 ml ofdimethylamine. The flask was sealed tightly and left standing at roomtemperature for 10 days. The dimethylamine and methanol were removed byrotary evaporation (60° C.; 30 mm). The residue was taken up in 150 mlof chloroform, washed with 3×50 ml dil sodium hydroxide, dried overanhydrous sodium sulfate, filtered and concentrated by rotaryevaporation (70° C.; 30 mm). The crude oil was dissolved in isopropylalcohol and treated with ethereal hydrogen chloride, which yielded 4.0 g(76%) of yellow crystals, m.p. 255° C. with decomposition.

Analysis: Calculated for C₁₄ H₂₂ N₃ OSCl: C, 53.23; H, 7.02; N, 13.30Found: C, 53.21; H, 7.15; N, 13.19

EXAMPLE 90 (Refer to Chart VII)2-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl[1,4]-oxazepino[6,7-c]quinolin-5(4H)-oneoxalate[1:1]

To a suspension of 19.4 g (35% in oil, 0.172 mole) of KH in 150 mltetrahydrofuran was added at a rapid drop 12.4 g (0.086 mole) of1-dimethylamino-4-methylamino-2-butanol. After 10 minutes, 20 g (0.086mole) of 3-carboxyethyl 4-chloroquinoline was added by a powder droppingfunnel over a period of 30 min. The mixture was stirred at roomtemperature overnight.

Approximately 50 ml of water was added to quench the reaction and themixture partitioned between isopropyl ether and water. The aqueous layerwas extracted again with 2×70 ml of isopropyl ether. The aqueous layerwas then continuously extracted for 15 hr with chloroform. Thechloroform layer was collected, filtered and concentrated by rotaryevaporation (80° C., 30 mm). The crude material (18 g) was purified byHPLC using silica gel as the stationary phase and 3%triethylamine/ethanol as the eluent. Approximately 4 g (15.6%) ofreasonably pure free base of the title compound was collected. A 1.5 gsample of the free base was reacted with 0.5 g oxalic acid in 10 ml ofethanol. The resulting crystals weighed 2 g and melted at 214°-218° C.

Analysis: Calculated for C₁₉ H₂₃ N₃ O₆ : C, 58.60; H, 5.95; N, 10.79.Found: C, 58.46; H, 6.10; N, 10.75.

EXAMPLE 912-[2-(Dimethylamino)-1-methylethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate[1:1]

To a suspension of 4.0 g (0.013 mole) of2-(2-chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionehydrochloride in 20 ml of methanol cooled in an ice bath was added 35 mlof dimethylamine previously collected at 0° C. The reaction flask wassealed tightly and left standing at room temperature for 10 days. Thesolvent was removed by rotary evaporation (80° C., water aspirator) andthe residue taken up in 150 ml of chloroform. The organic layer waswashed with 2×50 ml of dilute aqueous sodium hydroxide, dried overanhydrous sodium sulfate, filtered, and concentrated by rotaryevaporation. The crude residue was treated with oxalic acid in isopropylalcohol and left standing overnight at room temperature, yielding 3.1 g(65%) of yellow crystals, m.p. 211°-213° C.

Analysis: Calculated for C₁₆ H₂₃ O₅ N₃ S: C, 52.02; H, 6.18; N, 11.37.Found: C, 51.79; H, 6.34; N, 11.24.

EXAMPLE 922-[2-(Dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onedihydrochloride

Into a stainless steel bomb was placed 1.0 g sodium iodide, 5.0 g (0.017mole) of2-(2-chloropropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneand 40 ml of dimethylamine. The bomb was sealed tightly, placed in theoven at 60° C. and rolled continuously for 7 days. The bomb was allowedto stand at room temperature for several days. The residue was combinedwith that of a previous run of equal size and separated via columnchromatography using silica gel and eluting with ethanol and then with3% triethylamine/ethanol. The fractions containing the desired productwere combined and concentrated by rotary evaporation (80° C., 30 mm).The residue was taken up in 150 ml of chloroform and washed with 2×50 mldiluted sodium hydroxide. The chloroform was removed by rotaryevaporation (70° C., 30 mm) and the residue treated with etherealhydrogen chloride and hydrogen chloride in isopropyl alcohol. The whitecrystals which were collected weighed 3 g (28%), m.p. 173°-76° C.

Analysis: Calculated for C₁₄ H₂₃ N₂ O₂ Cl₂ : C, 50.01; H, 6.89; N,12.50. Found: C, 50.40; H, 7.04 N, 12.36.

EXAMPLE 932,3-Dihydro-4-methyl-2-[2-(2-methyl-1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate compound with 2-propanol[1:1:1]

To a suspension of 5.0 g (0.019 mole) of2-(chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 25 ml of absolute ethanol was added 3.5 g (0.04 mole) of2-methylpyrrolidine. The mixture was heated to reflux for 6.5 hr andleft standing at room temperature overnight. Mass spec and TLC showedpresence of starting materials. Approximately 5 g of potassium carbonatewas added and heating at reflux was continued for 24 hr. Ethanol wasremoved by rotary evaporation (70° C., 30 mm). The residue was taken upin 100 ml of methylene chloride and washed with 2×50 ml dil. aqueoussodium hydroxide. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated by rotary evaporation (70° C., 30mm). The residual syrup was dissolved in isopropyl aocohol and treatedwith fumaric acid affording 4.5 g (0.01 mole, 49.2%) of crude crystals.Two recrystallizations from isopropyl afforded 1.5 g (16.4%) of yellowcrystals, m.p., 92°-95° C.

Analysis: Calculated for C₂₃ H₃₅ N₃ O₆ S: C, 57.36; H, 7.33; N, 8.72.Found: C, 57.12; H, 7.30; N, 8.70.

EXAMPLE 942-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-9-(trifluoromethyl)-[1,4]oxazepino[6,7-c]quinolin-5(4H)-onefumarate[1:1]

To 55 ml of dimethylamine collected over an ice/methanol bath was added2.2 g (0.005 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino[6,7-c]quinolin-5(4H)-onehydrochloride. The flask was sealed tightly and left standing at roomtemperature for 6 days. After cooling to 0° C., the flask was opened andthe solvent allowed to evaporate at room temperature overnight. Theresidue was taken up in 100 ml of chloroform, washed with 3×33 ml of dilsodium hydroxide, dried over anhydrous sodium sulfate and concentratedto rotary evaporation (70° C., 30 mm). The residual oil was treated withfumaric acid in isopropyl alcohol and dried, giving 2.2 g (81%) of whitecrystals, m.p. 204°-05° C.

Analysis: Calculated for C₂₂ H₂₄ N₃ O₆ F₃ : C, 54.66; H, 5.00; N, 8.69.Found: C, 54.74; H, 5.12; N, 8.55.

EXAMPLE 952-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl[1,4]-oxazepino[6,7-b]quinolin-5(4H)-onefumarate hydrate[1:1:0.5]

To 40 ml of dimethylamine cooled to ˜0° C. in an ice water bath wasadded 3.85 g (0.013 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinoline-5(4H)-onein 25 ml of methanol. The reaction flask was sealed tightly and leftstanding at room temperature for 5 days. After cooling, the reactionflask was opened and the solvent allowed to evaporate in a stream ofair. The residue was taken up in 100 ml of chloroform and washed with2×50 ml of dilute aqueous sodium hydroxide. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated by rotaryevaporation (70°, 30 mm). The residual oil was treated with fumaric acidin isopropyl alcohol which afforded 3.7 g (67%) of white crystals, m.p.125°-130° C.

Analysis: Calculated for C₂₁ H₂₆ N₃ O₆.5 : C, 59.43; H, .17; N, 9.90.Found: C, 59.59; H, 6.36; N, 9.60.

EXAMPLE 962-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl[1,4]oxazepino[6,7-b]quinoline-5(4H)-thionefumarate compound with isopropanol hydrate [1:1:0.5:0.5]

To 45 ml of dimethylamine was added 0.95 g (0.003 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]quinoline-5(4H)-thione. The reaction flask was sealed tightly andleft standing at room temperature for 6 days. After cooling to 0° C.,the flask was opened and the solvent allowed to evaporate at roomtemperature. The residue was taken up in 50 ml of chloroform and washedwith 3×30 ml of dilute aqueous sodium hydroxiede. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated byrotary evaporation, yielding 0.94 g of syrup (99%). This was combinedwith 1.0 g of the same product from a previous run* and treated withfumaric acid in isopropyl alcohol affording 1.5 g of yellow crystals,m.p. 123°-26° C.

*The previous run was made in the same manner as above except thathydrochloride salt was collected. However, the hydrochloride saltpartially decomposed upon drying in a drying pistol at 82.5° C. Cautionshould be exercised not to heat the product above the boiling point ofacetone (56°-57° C.) while drying.

Analysis: Calculated for C₂₂.5 H₃₀ N₃ O₆ S: C, 57.43; H, 6.43; N, 8.92.Found: C, 57.60; H, 6.21; N, 9.02.

EXAMPLE 974-Ethyl-1,2,3,4-tetrahydro-2-[2-(4-hydroxy-4-phenyl-1-piperidinyl)-ethyl]-1-methyl-5H-1,4-benzodiazepin-5-onefumarate compound with 2-propanol [1:1:1]

A mixture of 13.4 g (0.05 mole) of2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one,8.85 g (0.05 mole) of 4-hydroxy-4-phenylpiperidine, and 14 g (0.1 mole)of potassium carbonate in 100 ml of n-butanol was refluxed for 18 hr andfiltered. The filtrate was concentrated and the residue partitionedbetween chloroform and dilute sodium hydroxide. The organic layer wasdried over anhydrous sodium sulfate and concentrated. The residue waschromatographed on a 4.5×45 cm Florisil® column eluting withchloroform-methanol mixture with a gradation from 100% to 84%chloroform. The fractions containing the pure product (as seen on tlcusing 95% chloroform-5% methanol on Florisil®) were combined andconcentrated. The residue was molecularly distilled at 250° C. and 0.22mm Hg. The fumarate salt was prepared in isopropyl alcohol andrecrystallized from isopropyl alcohol-water. Yield 5.8 g. (20%) m.p.128°-139° C.

Analysis: Calculated for C₃₂ H₄₅ N₃ O₇ : C, 65.85; H, 7.77 N, 7.20.Found: C, 64.85; H, 7.49 N, 7.06.

EXAMPLE 984-Ethyl-1-methyl-2-(2-morpholinoethyl)-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one

A solution of 30 g (0.112 mole) of2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-onein 70 ml of morpholine was refluxed for 3 hrs, concentrated on therotary evaporator and the residue partitioned between chloroform anddilute sodium hydroxide. The chloroform was dried over anhydrous sodiumsulfate and concentrated on the rotary evaporator. The residue wascrystallized twice from isopropyl ether containing a small amount ofethanol, m.p. 128°-148° C. Recrystallization from toluene gave 19.5 g(61%) of product, m.p. 128°-148° C.

Analysis: Calculated for C₁₈ H₂₇ N₃ O₂ : C, 68.11; H, 8.57; N, 13.24.Found: C, 68.29; H, 8.57; N, 13.26.

EXAMPLE 991,2,3,4-Tetrahydro-1-methyl-2-[(dimethylamino)methyl]-4-(1-methylethyl)-5H-1,4-benzodiazepin-5-one

A mixture of 5.0 g (0.02 mole) of2-chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-1,4-benzodiazepin-5-one,and 15.0 g (0.45 mole) of dimethylamine, and 200 ml of methanol wereplaced in a steel bomb and heated and stirred at 100° C. for 15 hr.After concentrating in vacuo, the residue partitioned between dilutesodium hydroxide solution and chloroform. The chloroform layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue crystallized in isopropyl ether and was recrystallized twicefrom the same. It weighed 29.0 g (68%), m.p. 93°-95° C.

Analysis: Calculated for C₁₆ H₂₅ N₃ O: C, 69.78; H, 9.15; N, 15.26.Found: C, 69.81; H, 9.01; N, 15.33.

EXAMPLE 1002-(2-Dimethylaminoethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one

A solution of 30 g (0.112 mole) of2-(2-chloroethyL)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-benzodiazepin-5-oneand 10 g (0.224 mole) of dimethylamine in 300 ml of ethanol was heatedat 125° C. for 8 hrs and concentrated. The residue was partitionedbetween chloroform and dilute sodium hydroxide. The chloroform was driedover anhydrous sodium sulfate, concentrated and distilled. Yield ofproduct was 20.5 g (66.5%), b.p. 175°-178°/0.1 mm.

Analysis: Calculated for C₁₆ H₂₅ N₃ O: C, 69.78; H, 9.15; N, 15.25.Found: C, 69.60; H, 9.17; N, 15.20.

EXAMPLE 1012,3-Dihydro-4-methyl-2-[2-(1-piperidinyl)ethyl]pyrido-[3,2-f][1,4]oxazepine-5(4H)-thionefumarate, hydrate compound with isopropyl alcohol [1:1:0.5:0.5]

To a suspension of 5.0 g (0.019 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 75 ml of absolute ethanol was added 10 ml of pyridine and the mixtureheated to 50° C. for 4 days. Ethanol was removed by rotary evaporation(70° C., 30 mm Hg). Piperidine was removed by rotary evaporation (80°C., 5 mm Hg) followed by azeotroping with 2×100 ml of toluene. Thesyrupy residue was taken up in 200 ml of isopropyl alcohol and heatedwith fumaric acid which afforded 5.2 g (57%) yellow crystals, m.p.133°-40° C.

Analysis: Calculated for C₂₁.5 H₃₂ N₃ O₆ S: C, 56.07; H, 7.00 N, 9.12.Found: C, 55.90; H, 6.86; N, 9.17.

EXAMPLE 1026-Chloro-2,3-dihydro-4-methyl-2-[2-(dimethylamino)ethyl]-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-onefumarate [1:0.5]

To 40 ml of freshly collected dimethylamine at -10° C. was added 4.0 g(0.015 mole) of6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one.The reaction flask was sealed tightly and left standing at roomtemperture for 5 days. After cooling to -10° C., the flask was openedand the dimethylamine allowed to evaporate overnight. The residue wastaken up in 100 ml of chloroform, washed with 2×30 ml of dilute sodiumhydroxide, dried over anhydrous sodium sulfate, filtered andconcentrated by rotary evaporation (70° C., 30 mm Hg). The residue wastreated with fumaric acid in isopropyl alcohol which uponcrystallization afforded 3.8 g (76.7%) of yellow crystals.

Analysis: Calculated for C₁₅ H₂₀ N₃ O₄ Cl: C, 52,70; H, 5.90; N, 12.29.Found: C, 52.67; H, 5.96; N, 12.01.

EXAMPLE 1032,3-Dihydro-4-methyl-6-dimethylamino-2-[2-(dimethylamino)ethyl]-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-onefumarate [1:1.5]

To 100 ml of freshly collected dimethylamine in a stainless steel bombwas added 4.5 g (0.016 mole) of6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one.The bomb was sealed tightly and placed in an oven at 100° C. for 18 hr.After cooling, the bomb was opened and the dimethylamine allowed toevaporate at room temperature. The residue was taken up in 150 ml ofchloroform, washed with 2×40 ml of dilute aqueous sodium hydroxide,dried over anhydrous sodium sulfate, filtered and concentrated by rotaryevaporation (70° C., 30 mm Hg). The residue was treated with fumaricacid in isopropyl alcohol. The resulting crystals were collected, driedovernight at room temperature, 0.5 mm Hg. The white crystals werecollected and afforded 4.2 g (56.3%) of the title compound, m.p.172°-75° C.

Analysis: Calculated for C₂₁ H₃₀ N₄ O₈ : C, 54.07; H, 6.48; N, 12.01.Found: C, 54.01; H, 6.58; N, 12.00.

EXAMPLE 1042,3-Dihydro-2-[2-(2,5-dihydro-1H-pyrrol-1-yl)ethyl]-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onefumarate [1:2]

To a solution of 10.0 g (0.041 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 50 ml of dimethylformamide was added 9.0 g (0.14 mole) of a mixtureof 3-pyrroline:pyrrolidine*, 3:1, v/v. The solution was heated to 65° C.under an N₂ blanket overnight. The solvent was removed by rotaryevaporation (70° C., 0.5 mm Hg). The syrupy residue was taken up in 100ml of chloroform, washed with 2×30 ml of dil. aqueous sodium hydroxide,dried over anhydrous sodium sulfate, filtered and concentrated by rotaryevaporation (60° C., 30 mm). The residue was azetroped with 3×100 ml oftoluene. The residue was purified by HPLC to separate out thepyrrolidine derivative, eluting with 2% triethylamine in methylenechloride (v/v). Fractions with similar TLC's were combined andconcentrated by rotary evaporation. To the residue was added ˜100 ml oftoluene and the mixture heated to 70° C. and filtered hot. Approximately0.2-0.3 g of hygroscopic crystals were collected. The toluene wasremoved by rotary evaporation (70° C., 30 mm Hg). The residual syrup wastreated with fumaric acid in isopropyl alcohol. Two crops of crystalswere collected, combined and recrystallized together giving 4.6 g(22.1%) of white crystals, m.p. 158°-159° C.

Analysis: Calculated for C₂₃ H₂₇ N₃ O₁₀ : C, 54,65; H, 5.38; N, 8.31.Found: C, 54.58; H, 5.49; N, 8.30.

EXAMPLE 1052,3-Dihydro-2-(2,5-dihydro-1H-pyrrol-1-yl)ethyl]-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionefumarate [1:1]

To a solution of 9.0 g (0.035 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 50 ml of dry dimethylformaide was added 10.0 g (0.141 mole) ofpyrroline/pyrrolidine*, 3:1, v/v, and the mixture heated to 60° C. for18 hr. The solvent was removed by rotary evaporation (70° C., 0.5 mm Hg)and the syrupy residue purified by HPLC separating out the pyrrolidinederivative eluting with 2% triethylamine in methylene chloride (v/v)over silica gel. Fractions having similar TLC's were combined andconcentrated by rotary evaporation. The syrupy residue was treated withfumaric acid in isopropyl alcohol which afforded 4.0 g (28.1%) ofcrystals. One recrystallization from isopropyl alcohol afforded ananalytical sample, m.p. 143°-45° C.

Analysis: Calculated for C₁₉ H₂₃ N₃ O₅ S: C, 56.28; H, 5.72; N, 10.36.Found: C, 56.03; H, 5.23; N, 10.22.

EXAMPLE 1062-[2-(1-Azetidinyl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f[[1,4]oxazepin-5(4H)-oneoxalate hydrate [1:1:0.5]

To a solution of 4.1 g (0.017 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 50 ml of dimethylformamide under nitrogen was added asolution/suspension of 0.7 g (60% in oil, 0.017 mole) of sodium hydridein 0.10 ml of dimethylformamide to which 1.0 g (0.017 mole) of azetidinein 20 ml of dimethylformamide had been added and allowed to stir undernitrogen atmosphere until hydrogen evolution ceased (15 min). Thereaction mixture was stirred for 18 hr under nitrogen at roomtemperature. The solvent was removed by rotary evaporation (70° C., 0.5mm Hg) and the residue taken up in 100 ml of chloroform, washed with3×30 ml dil. aqueous sodium hydroxide, dried over anhydrous sodiumsulfate, filtered and concentrated by rotary evaporation. The residuewas treated with oxalic acid in isopropyl alcohol which afforded 1.3 g(21.2%) of white crystals, m.p. 172°-174° C. with slight decomposition.

Analysis: Calculated for C₁₆ H₂₂ N₃ O₆.5 : C, 53.33; H, 6.15; N, 11.66.Found: C, 53.73; H, 6.11; N, 11.67.

EXAMPLE 107 (Refer to Chart VIII)2-[(Dimethylamino)methyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-onefumarate [1:1]

Dimethylamine 22.6 g, 40% solution (0.2 mole) was added dropwise to asolution of 16 ml of epichlorohydrin (0.2 mole) in 100 ml of methanol at5° C. stirring in an ice bath. After two hours at 5° C. a chilledsolution of 86 ml methylamine of 40% solution (1 mole) was poured intothe reaction mixture. Stirring was continued in ice bath for one hourand then room temperature overnight. The solvents were evaporated andthe clear oil was pumped under vacuum at 75° C. for 1.5 hr to give 28.23g (˜84% yield) of 1-dimethylamino-3-methylamino-2-propanol hydrochloride(I) as the main product.

Compound I, 21.4 g (0.143 mole) and 22.6 g of 2- chloronicotinic acid(0.143 mole) were stirred in 150 ml acetonitrile and 60 ml water as atwo-layer system. Dicyclohexylcarbodiimide, 33 g (0.16 mole) dissolvedin 90 ml of acetonitrile was added in four portions. After the additionof the second portion, an ice bath was necessary for controlling thetemperature at around 25° C. Two and a half hours later, 10 g of2-chloronicotinic acid was added to the reaction mixture and 15 g ofdicyclohexylcarbodiimide in 200 ml of acetonitrile was added in anotherhour. The reaction was stirred at room temperature overnight.Concentrated hydrochloric acid was added to the reaction mixture to pH 2in order to convert the excess carbodiimide to urea. The white solid wasremoved by filtration and rinsed with aqueous acetonitrile. The filtrateand washings were evaporated to a paste which was partitioned betweenmethylene chloride and potassium carbonate solution. The aqueous layerwas extracted two more times with methylene chloride. The methylenechloride solutions were back washed with sodium chloride solution, driedover anhydrous sodium sulfate and evaporated to give 56 g of oil. Thisoil was chromatographed on 250 g of silica gel eluting with methanol togive 26.97 g of light brown oil containing mainly the2-chloronicotinamide of compound I.

The 26.97 g of compound obtained from chromatography was dissolved in200 ml of toluene and heated to distill out about 40 ml solvent and thenrefluxed under a Dean-Stark trap for one half hour. Sodium hydride, 15 g(50% suspension in mineral oil, 0.3 mole) was added portionwise to thetoluene solution at room temperature. The mixture was then heated toreflux for 20 min. The cooled mixture was treated with isopropanol andcelite and then filtered. The filtrate was acidified with hydrogenchloride solution in isopropanol. The white solid thus formed wascollected by filtration, rinsed with isopropyl alcohol-isopropyl etherand dried under nitrogen. This material weighed 11 g and absorbedmoisture from air readily. Some second and third crop materials wereobtained from the mother liquor and washings. All three crops werecombined and dissolved in water, the solution was made basic with excessamount of potassium carbonate and then extracted three times withmethylene chloride; the methylene chloride solutions were back washedwith saturated sodium chloride solution, dried over magnesium sulfateand treated with activated charcoal, filtered and evaporated to give 8.8g of brown oil, the free base of the title compound.

A 1.9 g sample of the brown oil was dissolved in methanol and kept warmon steam bath. Fumaric acid was added and the solution was concentratedto a small volume. Excess amount of acetone was added to crystallize outthe fumarate salt. The salt was recrystallized once to 1.4 g of whitesolid, m.p. 150°-151° C.

Analysis: Calculated for C₁₆ H₂₁ N₃ O₆ : C, 54.70; H, 6.02; N, 11.96.Found: C, 54.69; H, 6.07; N, 11.88.

EXAMPLE 1082-[(Dimethylamino)methyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate [2:1]

2-[(Dimethylamino)methyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one,4.8 g, was dried azotropically in about 50 ml of toluene. To the warmsolution was added Lawesson reagent (Aldrich #22, 743-9, 4.9 g) and thereduction mixture was kept at reflux for two hours. On contact withconcentrated potassium carbonate solution, the reaction mixture became athree-layer system; both the aqueous layer and the toluene layercontained product but not the third gummy layer. The layers wereseparated and the aqueous layer was extracted three times with methylenechloride which was back washed with saturated sodium chloride solution,combined with the toluene layer, dried over sodium sulfate andevaporated to 5.25 g oil. This oil was dissolved in methanol and 2.45 gfumaric acid was added. With heating and stirring, isopropanol was addedto the point of cloudiness and then left stirring overnight. The mixturefirst deposited out a layer of brown gummy material and thencrystallized to a yellow powder. The yellow powder, 2.85 g, wascollected and recrystallized from methanol, m.p. 178°-179° C.

Analysis: Calculated for C₁₄ H₁₉ N₃ O₃ S: C, 54.35; H, 6.19; N, 13.58.Found: C, 54.21; H, 6.20; N, 13.53.

EXAMPLE 109 (Refer to Chart VIII)2-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f][1,4]oxazepin-5(4H)-one

To a cold (ice bath) solution of 3.2 g (0.02 mole) of 2-chloronicotinicacid and 3 g (0.02 mole) of 1-dimethylamino-4-methylamino-2-butanol in25 ml of methylene chloride was added 4.55 g (0.022 mole) ofdicyclohexyl carbodiimide. Methanesulfonic acid, 1.8 ml, was added tobring the pH to 6. White solid appeared in the reaction mixture. The icebath was removed after 1 hr and the mixture was allowed to stand at roomtemperature overnight. The white solid was removed by filtration and thefilter cake rinsed with methylene chloride. The combined filtrate andwash was extracted twice with 0.6N hydrochloric acid (15 ml and 10 ml).To the combined acidic aqueous extracts was added 6 g of potassiumbicarbonate and methylene chloride with stirring. The layers wereseparated and the aqueous basic layer was extracted with methylenechloride. The methylene chloride layers were combined, dried overanhydrous sodium sulfate and evaporated to give 4.5 g brown oil whichwas predominantly2-chloro-N-[4-(dimethylamino)-2-hydroxybutyl]-N-methyl-3-pyridinecarboxamide.

The 4.26 g (0.0149 mole) of the foregoing prepared 3-pyridinecarboxamidewas mixed with 50 ml of toluene and the mixture was heated to distilloff about 20 ml of solvent and then kept at reflux using a Dean-Starktrap to collect moisture. The temperature of the solution was loweredsomewhat and 0.864 g (0.018 mole) of sodium hydride in mineral oil wasadded to produce gentle reflux. After a total of 45 min, the mixture wascooled andd to it was added 0.5 ml of isopropyl alcohol and 0.5 ml ofwater. Carbon dioxide was bubbled in to convert the sodium hydroxideproduced to sodium bicarbonate. The mixture was then azeotroped todryness using a Dean-Stark trap. Some acetonitrile was added to the hotmixture. After cooling, the mixture was filtered through celite rinsingwith acetonitrile. The filtrate was evaporated to give a mixture of thetitle product and a trace of mineral oil. The amount of title productobtained was 3.45 g (93% yield). The NMR and Mass Spec agreed with thatof the free base of the compound prepared in Example 10.

EXAMPLE 1102-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinolin-5(4)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinolin-5(4H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1112-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinoline-5(4H)-thionehydrochloride

Following the procedure of Example 31,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinoline-5(4H)-thioneis reacted with dimethylamine to give the title compound.

EXAMPLE 1122-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g]isoquinolin-5(4H)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g]isoquinolin-5(4H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1132-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepine[6,7-g]isoquinoline-5(4H)-thionehydrochloride

Following the procedure of Example 31,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g]isoquinoline-5(4H)-thioneis reacted with dimethylamine to give the title compound.

EXAMPLE 1142-[2-(Dimethylamino)ethyl]-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-b]quinolin-5(4H)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1152-[2-(Dimethylamino)ethyl]-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thionehydrochloride

Following the procedure of Example 31,2-(2-chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thioneis reacted with dimethylamine to give the title compound.

EXAMPLE 1162-[2-(Dimethylamino)ethyl]-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]qiinolin-5(4H)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]-quinolin-5(4H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1172-[2-(Dimethylamino)ethyl]-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thionehydrochloride

Following the procedure of Example 31,2-(2-chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h)quinoline-5(4H)-thioneis reacted with dimethylamine to give the title compound.

EXAMPLE 1184-[2-(Dimethylamino)ethyl]-3,4-dihydro-2-methyl-[1,4]-oxazepino[6,7-f]quinolin-1(2H)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-3,4-dihydro-2-methyl[1,4]-oxazepino[6,7-f]quinolin-1(2H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1194-[2-(Dimethylamino)ethyl]-3,4-dihydro-2-methyl[1,4]-oxazepino[6,7-f]quinoline-1(2H)-thionehydrochloride

Following the procedure of Example 31,4-(2-chloroethyl)-3,4-dihydro-2-methyl-[1,4]-oxazepino[6,7-f]quinoline-1(2H)-thione is reacted with dimethylamine to give the title compound.

EXAMPLE 1202-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-oneoxalate

Following the procedure of Example 21,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinolin-5(4H)-oneis reacted with dimethylamine to give the title compound.

EXAMPLE 1212-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thionehydrochloride

Following the procedure of Example 31,2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thioneis reacted with dimethylamine to give the title compound.

EXAMPLE 1222-[2-(1-Azetidinyl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate hydrate [1:1:0.5]

To a solution of 5.0 g (0.021 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onedissolved in 40 ml of dimethylsulfoxide was added 8.7 g (0.063 mole) ofpotassium carbonate followed by 1.40 g (0.025 mole) of azetidine. Themixture was stirred for 4 days at room temperature*. Another 0.5 g(0.009 mole) of azetidine was added and stirring continued for 24 hr.Another 0.7 g (0.012 mole) of azetidine was added and the mixture wasstirred for 24 hr. The potassium carbonate was filtered off and thedimethyl sulfoxide was removed from the filtrate by rotary evaporationat 90° C., 0.5 mm Hg. The residue was taken up in 100 ml of methylenechloride and the solution was washed with two 30 ml portions of waterfollowed by 30 ml of dilute aqueous sodium hydroxide. The organic layerwas dried over magnesium sulfate, filtered and concentrated by rotaryevaporation. The residual syrup was reacted with oxalic acid inisopropyl alcohol giving 3.3 g (44%) of white crystals, m.p. 170°-172°C. ¹ HNMR analysis was essentially the same as for the same compoundobtained in Example 106.

EXAMPLE 1232-[2-(1-Azetidinyl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate

To 5.0 g (0.0914 mole) of2-(2-chloroethyl)-2,5-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionedissolved in 50 ml of dimethylsulfoxide was added 8.04 g (0.058 mole) ofpotassium carbonate and 1.21 g (0.021 mole) of azetidine. The reactionmixture was stirred at room temperature for 8 hr after which was added0.5 g (0.009 mole) of azetidine and the mixture was stirred overnight atroom temperature. An additional 0.3 g (0.005 mole of azetidine was addedand stirring was continued for 24 hr. The mixture was filtered andsolvent removed by rotary evaporator at 80° C., 0.5 mm Hg. The residuewas taken up in 100 ml of chloroform and the solution was washed withtwo 30 ml portions of dilute aqueous sodium hydroxide. The organic layerwas dried over magnesium sulfate, filtered and concentrated by rotaryevaporator. The residue was reacted with fumaric acid in isopropylalcohol to give 2.5 g (31%) of pale yellow crystals, m.p. 122°-126° C.

EXAMPLE 1242-[2-(1-Azetidinyl)ethyl]-7-chloro-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thioneoxalate [1:1:0.5]

To 5.0 g (0.017 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thionedissolved in 50 ml of dimethyl sulfoxide was added 7 g of crushedpotassium carbonate and 1.47 g (0.025 mole of azetidine. The mixture wasstirred for 3 days at room temperature. Because of incomplete reaction,0.5 g (0.009 mole) of azetidine was added and the reaction stirred anadditional 24 hrs at room temperature. The potassium carbonate wasfiltered off and dimethylsulfoxide removed by rotary evaporation at 90°C. and 0.5 mm Hg. The residue was taken up in 100 ml of chloroform andwashed with 2×30 ml of dil. sodium hydroxide and 2×30 ml of water. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated by rotary evaporation. Treatment of the residual syrup inisopropyl alcohol with oxalic acid gave 3.3 g (47%) of yellow crystals,m.p. 121°-126° C.

Analysis: Calculated for C₁₇ H₂₂ N₂ O₅.5 SCl: C, 49.81; H, 5.41; N,6.83. Found: C, 49.64; H, 5.20; N, 6.72.

EXAMPLE 125(S)-2-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionehydrochloride [1:2]

Procedure: A 10 g (0.042 mole) sample of(S)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionewas treated with 50 ml of methylamine and sealed in a flask. Theresulting solution was stirred at 25° C. for 48 hr. The excess amine wasallowed to evaporate and the residue was partitioned between chloroformand dilute sodium hydroxide. The chloroform was dried over sodiumsulfate and concentrated. The residue was dissolved in acetonitrile andtreated with ethereal hydrogen chloride. The resulting crystals wererecrystallized from isopropyl alcohol-ethyl alcohol. Yield of titlecompound was 5 g (36%), m.p. 170°-179° C. [α]_(D) ²⁵ =+20.8 (water).

Analysis: Calculated for C₁₃ H₂₁ N₃ OSCl₂ : C, 46.16; H, 6.26; N, 12.42.Found: C, 46.03; H, 6.35; N, 12.38.

EXAMPLE 126(R)-2-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionehydrochloride [1:2]

Procedure: A 10 g (0.042 mole) sample of(R)-2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionewas treated with 50 ml of methylamine and sealed in a flask. Theresulting solution was stirred at 25° C. for 48 hr. The excess amine wasallowed to evaporate and the residue was partitioned between chloroformand dilute sodium hydroxide. The chloroform was dried over sodiumsulfate and and concentrated. The residue was dissolved in acetonitrileand treated in an acetonitrile solution of hydrogen chloride. Theresulting crystals were recrystallized from ethanol. Yield of titlecompound was 7 g (50%); m.p. 170°-176° C.; [α]_(D) ²⁵ =-21.6 (water).

Analysis: Calculated for C₁₃ H₂₁ N₃ OSCl₂ : C, 46.16; H, 6.26; N, 12.42.Found: C, 46.02; H, 6.36; N, 12.36.

EXAMPLE 1272-[2-(1-Azetidinyl)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionefumarate, 2-propanol [1:1:0.33]

To a solution of 5.0 g (0.0195 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thionein 40 ml of dimethylsulfoxide was added 8.0 g of crushed potassiumcarbonate followed by 1.40 g (0.023 mole) of azetidine. The reactionflask was stoppered and stirred at room temperature for 24 hr and 0.8 g(0.014 mole) of azetidine was added. After 24 hr, another 0.4 g (0.007mole) of azetidine was added and stirring at room temperature continued.After 24 hr, the reaction mixture was diluted with 100 ml of water andextracted with 3×100 ml of benzene. The benzene extracts were combined,washed with 3×50 ml of water and 50 ml of saturated sodium chloride,dried over sodium sulfate, filtered, and concentrated by rotaryevaporation. The residue was treated with fumaric acid in isopropylalcohol which yielded 4.2 g (49.5%) of yellow crystals, m.p. 106°-22° C.with decomposition.

Analysis: Calculated for C₁₈ H₂₃ N₃ O₅ S*: C, 54.95; H, 5.89; N, 10.68.Found: C, 53.73; H, 6.11; N, 9.75.

EXAMPLE 1287-Chloro-2-[2-(diethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To a suspension of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-onein 50 ml of absolute ethanol was added 2.26 ml (0.022 mole) ofdiethylamine and the mixture heated to reflux. (Complete dissolutionoccurred). After 1 hr, another 2.26 ml (0.022 mole) of diethylamine wasadded followed by 5.0 ml (0.049 mole) and heating continued for 2 morehours. TLC (ethylacetate/methanol/conc. ammonium hydroxide, 7:2:1,v/v/v) still showed presence of starting material; another 2.26 ml(0.022 mole) of diethylamine was added and heating continued for 15 hrat reflux. Solvent was removed by rotary evaporation (60° C., 30 mm Hg)and the residue taken up in methylene chloride, washed twice with diluteaqueous sodium hydroxide and once with water. The organic layer wasdried over sodium sulfate, filtered and concentrated by rotaryevaporation, and azeotroped once with toluene. The oil was treated withoxalic acid in isopropyl alcohol which yielded 6.7 g (76%) of whitecrystals, m.p. 163°-164° C.

Analysis: Calculated for C₁₇ H₂₄ N₃ O₆ Cl: C, 50.81; H, 6.02; N, 10.40.Found: C, 50.83; H, 6.13; N, 10.50.

EXAMPLE 1292-[2-(1-Azetidinyl)ethyl]-7-chloro-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To a solution of 6 g (0.022 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-onein 40 ml of dimethyl sulfoxide was added 8.0 g of crushed potassiumcarbonate and 1.5 g (0.026 mole) of azetidine. The reaction was stirredat room temperature for 24 hr. After checking ty TLC [7:2:1 by volumeethyl acetate:methanol:conc. ammonium hydroxide, another 0.4 g (0.007mole) of azetidine was added. Two days later, another 0.5 g (0.0087mole) of azetidine was added and the mixture stirred for 24 hr more. Thereaction mixture was diluted with 100 ml of water and extracted with4×100 ml of benzene. The organic extracts were combined, washed with3×100 ml of water, dried over sodium sulfate, filtered, and concentratedby rotary evaporation. The syrupy residue was treated with oxalic acidin isopropyl alcohol. This yielded 4.2 g (56.5%) of white material, m.p.169°-174° C. with decomposition.

Analysis: Calculated for C₁₆ H₂₀ N₃ O₆ Cl: C, 49.81; H, 5.23; N, 10.89.Found: C, 49.70; H, 5.33; N, 10.79.

EXAMPLE 1307-Chloro-2,3-dihydro-4-methyl-2-[2-methyl(phenylmethyl)amino]pyrido[3,2-f][1,4]oxazepin-5(4H)-oneoxalate [1:1]

To a solution of 6.0 g (0.022 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-onein 50 ml of absolute ethanol was added 5.3 g (0.044 mole) ofbenzylmethylamine and the mixture heated to reflux for three days. Thesolvent was removed by rotary evaporation, and the residue was taken upin 100 ml of methylene chloride, which was subsequently washed with 2×50ml of dilute sodium hydroxide and 50 ml water, dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. Residualbenzylmethylamine was removed at 95° C., 0.5 mm Hg. However, the massspectrum now showed starting material; therefore, the residue was takenup in 50 ml of absolute ethanol. To the resulting solution was added 2.7g (0.022 mole) of benzylmethylamine and the mixture heated to reflux for24 hrs. The reaction mixture was subjected to the same work-up asmentioned before. The syrup was treated with oxalic acid in isopropylalcohol. The resulting crystals were recrystallized fromethanol/isopropyl alcohol to give 4.7 g (47.9%) of white crystals, m.p.176°-179° C.

Analysis: Calculated for C₂₁ H₂₄ N₃ O₆ Cl: C, 56.07; H, 5.38; N, 9.34.Found: C, 56.07; H, 5.46; N, 9.28.

EXAMPLE 1317-Chloro-2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]pyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To 6 g (0.022 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-onewas added 80 ml of 30% monomethylamine (by weight) in absolute ethanol.The reaction flask was sealed and left standing at room temperature for˜4 days. The solvent was evaporated in a stream of air. The residue wastaken up in 200 ml of methylene chloride, washed with 2×50 ml dilutedaqueous sodium hydroxide and 50 ml of water, dried over sodium sulfate,filtered, and concentrated by rotary evaporation (60° C., 20 mm Hg). Theresidue was treated with oxalic acid in isopropyl alcohol which yielded4.5 g (67%) of white crystals, m.p. 109°-113° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₈ N₃ O₆ Cl: C, 46.74; H, 5.04; N, 11.68.Found: C, 46.73; H, 5.27; N, 11.31.

EXAMPLE 1327-Bromo-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To 60 ml of freshly collected dimethylamine was added 6.0 g (0.019 mole)of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one.The flask was sealed and left standing at room temperature for threedays. The dimethylamine was evaporated in a stream of air. The residuewas taken up in 200 ml of methylene chloride, washed with 2×50 mldiluted aqueous sodium hydroxide and 50 ml of water, dried over sodiumsulfate, filtered and concentrated by rotary evaporation at 60° C., 30mm Hg. The residue was treated with oxalic acid in isopropyl alcoholwhich afforded 4.6 g (59%) of white crystals, m.p. 165°-167° C.

Analysis: Calculated for C₁₅ H₂₀ O₆ N₃ Br: C, 43.08; H, 4.82; N, 10.05.Found: C, 43.10; H, 4.87; N, 10.04.

EXAMPLE 1332-[2-(1-Azetidinyl)ethyl]-7-bromo-2,3-dihydro-4-methylpyrido[2,3-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To 40 ml of dimethylsulfoxide was added 6.0 g (0.019 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one,8.0 g of crushed potassium carbonate, and 1.28 g (0.023 mole) ofazetidine. The reaction mixture was sealed and stirred at roomtemperature for two days, after which 0.5 g (0.009 mole) more azetidinewas added. Stirring was continued for 24 hr and still another 0.5 g(0.009 mole) of azetidine was added. After 24 hr, the reaction mixturewas diluted with 200 ml of water, dried over sodium sulfate, filtered,and concentrated by rotary evaporation (60° C., 30 mm Hg). The residualsyrup was treated with oxalic acid in isopropyl alcohol to give 4.9 g(61%) of white crystals, m.p. 163°-169° C. with decomposition.

Analysis: Calculated for C₁₆ H₂₀ N₃ O₆ Br: C, 44.67; H, 4.69; N, 9.77.Found: C, 44.59; H, 4.77; N, 9.70.

EXAMPLE 1347-Bromo-2,3-dihydro-4-methyl-2-[2-[methyl(phenylmethyl)amino]ethyl]pyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To 6.0 g (0.019 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 40 ml of absolute ethanol was added 4.54 g (0.038 mole) ofbenzylmethylamine and the solution heated to reflux. After 2 days,another 2.75 g (0.023 mole) of benzylmethylamine was added and heatingcontinued for 24 hr. Solvent was removed by rotary evaporation at 70°C., 30 mm Hg, the residual syrup taken up in 200 ml of methylenechloride, washed with 2×50 ml dilute aqueous sodium hydroxide and 50 mlof water, dried over sodium sulfate, filtered, and concentrated byrotary evaporation (60° C., 30 mm Hg). Most of the remainingbenzylmethylamine was removed at 100° C., 0.5 mm over 2.5 hr periods.The residual syrup was treated with oxalic acid in isopropyl alcohol.Recrystallization from ethanol/isopropyl alcohol gave 5.3 g (57%) ofwhite crystals, m.p. 180°-183° C.

Analysis: Calculated for C₂₁ H₂ N₃ O₆ Br: C, 51.02; H, 4.89; N, 8.50.Found: C, 50.87; H, 5.00; N, 8.49.

EXAMPLE 1357-Bromo-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To 50 ml of freshly collected dimethylamine was added 5.5 g (0.0164mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione.The reaction flask was sealed tightly and left standing at roomtemperature for three days. The dimethylamine was evaporated in a streamof air and the residue taken up in 200 ml of methylene chloride whichwas washed with 2×50 ml of dilute aqueous sodium hydroxide and 50 ml ofwater, dried over sodium sulfate, filtered and concentrated by rotaryevaporation. The residual syrup was treated with oxalic acid inisopropyl alcohol which gave 5.1 g (72%) of yellow crystals, m.p.145°-151° C.

Analysis: Calculated for C₁₅ N₂₀ N₃ O₅ SBr: C, 41.48; H, 4.54; N, 9.68.Found: C, 41.38; H, 4.66; N, 9.71.

EXAMPLE 1362-[2-(1-Azetidinyl)ethyl]-7-bromo-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

Into 40 ml of dimethylsulfoxide was dissolved 5.5 g (0.0164 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionefollowed by addition of 8.0 g of potassium carbonate and 1.40 g (0.0246mole) of azetidine. The mixture was stirred 24 hr and 0.5 g (0.009 mole)of azetidine was added. After 24 hr, still another 0.5 g (0.009 mole) ofazetidine was added. After 24 hr, the reaction mixture was diluted with200 ml of water and extracted with 3×75 ml benzene. The organic extractswere combined and washed with 3×50 ml of water, dried over sodiumsulfate, filtered and concentrated by rotary evaporation. Treatment ofthe residual syrup with oxalic acid in isopropyl alcohol afforded 5.85 g(80%) of yellow crystals, m.p. 161°-170° C. with decomposition.

Analysis: Calculated for C₁₆ H₂₀ N₃ O₅ SBr: C, 43.06; H, 4.52; N, 7.42.Found: C, 43.15; H, 4.62; N, 9.50.

EXAMPLE 1377-Chloro-2,3-dihydro-4-methyl-2-[2-(1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-thionefumarate [1:1]

To a suspension of 4.75 g (90.0164 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein absolute ethanol was added 3.4 ml (0.04 mole) of pyrrolidine. Thesuspension was heated to reflux (complete solution occurred) for 3 hrand another 1.7 ml (0.2 mole) of pyrrolidine was added. After 5 hr moreat reflux, solvent was removed by rotary evaporation and azeotropedtwice with toluene. The residue was taken up in 100 ml of methylenechloride, washed with 2×50 ml of dilute aqueous sodium hydroxide and 50ml of water, dried over sodium sulfate, filtered, and concentrated byrotary evaporation (60° C., 30 mm Hg) and stripped further at 85° C.,0.5 mm Hg for 2 hr. The residue was treated with fumaric acid inisopropyl alcohol. The resulting crystals were recrystallized fromethanol/isopropyl alcohol to give 5.1 g (70%) of yellow crystals, m.p.172°-173° C.

Analysis: Calculated for C₁₉ H₂₄ N₃ O₅ SCl: C, 51.64; H, 5.47; N, 9.51.Found: C, 51.49; H, 5.58; N, 9.53.

EXAMPLE 1387-Chloro-2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To 60 ml of 30% monomethylamine in ethanol was added 4.75 g (0.016 mole)of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione.The reaction flask was sealed tightly and left standing at roomtemperature. After 8 days, the solvent was removed by rotaryevaporation. Another 40 ml of 30% monomethylamine in ethanol was addedsince some starting material remained. After 2 days, the solvent wasevaporated in a stream of air and the residue taken up in 100 ml ofmethylene chloride. The organic layer was washed twice with dilutesodium hydroxide and once with water, dried over sodium sulfate,filtered, and concentrated by rotary evaporation. The residue wastreated with oxalic acid in isopropyl alcohol. The resulting crystalswere recrystallized from isopropyl alcohol/ethanol to give 0.85 g(13.8%) of yellow crystals, m.p. 112°-129° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₈ N₃ O₅ SCl: C, 44.74; H, 4.83; N, 11.18.Found: C, 44.69; H, 5.20; N, 11.01.

EXAMPLE 1392-[2-(1-Azetidinyl]ethyl-7-chloro-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To a solution of 4.75 g (0.0164 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 40 ml of dimethyl sulfoxide was added 8.0 g of crushed potassiumcarbonate and 1.4 g (0.0246 mole) of azetidine. The flask was sealed andstirred at room temperature for 24 hr after which an additional 0.6 g(0.011 mole) of azetidine was added. After 24 hr, another 0.5 (0.009mole) of azetidine was added and stirring continued at room temperature.After 48 hr, the entire reaction mixture was diluted with 200 ml ofwater and extracted with 2×100 ml of benzene. The organic extracts werecombined, washed with 3×100 ml of water and 1×100 ml saturated sodiumchloride, dried over sodium sulfate, filtered, and concentrated byrotary evaporation (65° C., 30 mm Hg). The residue was treated withoxalic acid in isopropyl alcohol to give 5.4 g (82%) of yellow crystals,m.p. 146°-150° C.

Analysis: Calculated for C₁₆ H₂₀ N₃ O₅ SCl: C, 47.82; H, 5.02; N, 10.46.Found: C, 47.66; H, 5.12; N, 10.30.

EXAMPLE 1407-Bromo-2,3-dihydro-4-methyl-2-[2-[methyl(phenylmethyl)amino]ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To a suspension of 5.00 g (0.015 mole) of7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 40 ml of absolute ethanol was added 3.63 g (0.030 mole) ofbenzylmethylamine. The reaction mixture was heated to reflux. After 3hr, an additional 1.8 g (0.015 mole) of benzylmethylamine was added andheating continued for 24 hr. The solvent was removed by rotaryevaporation at 60° C., 30 mm Hg) followed by 75° C., 0.5 mm Hg for 1 hr.The residue was taken up in 100 ml of methylene chloride, washed with2×50 ml dilute sodium hydroxide and 50 ml water, dried over sodiumsulfate, filtered, concentrated by rotary evaporation, and subjected 0.5mm Hg vac at 75° C. for 2 hr. The residue was treated with oxalic acidin isopropyl alcohol. The resulting crystals were recrystallized fromisopropyl alcohol/ethanol to give 5.9 g (77%) of yellow crystals, m.p.192°-203° C. with decomposition.

Analysis: Calculated for C₂₁ H₂₄ N₃ O₅ SBr: C, 49.42; H, 4.74; N, 8.23Found: C, 49.40; H, 4.77; N, 8.22

EXAMPLE 1417-Chloro-2-[2-(diethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionefumarate [1:1]

To a suspension of 4.75 g (0.0164 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thionein 40 ml of absolute ethanol was added 10 ml of diethylamine and thereaction mixture was heated to reflux. After 3 hr, another 5 ml ofdiethylamine was added and heating continued for 24 hr. Another 2 ml ofdiethylamine was added and heating was continued for 2 hr. The solventwas then removed by rotary evaporation and the residue azeotroped oncewith toluene and subjected to 0.5 mm Hg vacuum at 70° C. for 20 min. Thesyrupy residue was taken up in 100 ml of methylene chloride, washed with2×50 ml of dilute sodium hydroxide, dried over sodium sulfate, filteredand concentrated by rotary evaporation. The residue syrup was treatedwith fumaric acid in isopropyl alcohol giving 3.86 g (53%) of yellowcrystals, m.p. 141°-143° C.

Analysis: Calculated for C₁₉ H₂₆ N₃ O₅ SCl: C, 51.40; H, 5.90; N, 9.47.Found: C, 51.20; H, 5.96; N, 9.42.

EXAMPLE 142 7-Chloro-2,3-dihydro-4-methyl-2-[2-[methyl(phenylmethylamino]ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-thione oxalate [1:1]

To a suspension of 4.75 g (0.016 mole) of7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 50 ml of absolute ethanol was added 4.00 g (0.033 mole) ofbenzylmethylamine and the mixture heated to reflux. After 24 hr, anadditional 2.00 g (0.017 mole) of benzylmethylamine was added and heatcontinued. Still another 2.00 (0.017 mole) of benylmethylamine was addedand heating continued for 24 hr. The solvent was removed by rotaryevaporation at 70° C., 30 mm Hg, and the residue taken up in 100 ml ofmethylene chloride, washed with 1N sodium hydroxide, dried over sodiumsulfate, filtered, concentrated by rotary evaporation (70° C., 30 mmHg). The syrupy residue was then subjected to 100° C., 0.5 mm Hg, andsubsequently treated with oxalic acid in isopropyl alcohol. Theresulting crystals were recrystallized from ethanol and isopropylalcohol to give 4.9 g (64%) of yellow crystals.

Analysis: Calculated for C₂₁ H₂₄ N₃ O₅ SCl: C, 54.13; H, 5.19; N, 9.02.Found: C, 53.99; H, 5.25; N, 8.93.

EXAMPLE 1432-[2-(Ethylmethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-oneoxalate [1:1]

To a solution of 5.00 g (0.021 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onein 40 ml of absolute ethanol was added 10 ml of ethylmethylamine. Thereaction flask was sealed and stirred at room temperature for 7 days.The reaction mixture was then heated on low heat for 14 hr after whichwas added 2.5 ml of ethylmethylamine and heating continued for 15 hr.The solvent was then removed by rotary evaporation and syrupy residuetaken up in methylene chloride which was washed twice with diluteaqueous sodium hydroxide dried over sodium sulfate, filtered, andconcentrated by rotary evaporation. The residue was treated with oxalicacid in isopropyl alcohol which afforded 5.0 g (74.5%) of whitecrystals, m.p. 133° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₆ : C, 54.38; H, 6.56; N, 11.89.Found: C, 54.19; H, 6.68; N, 11.83.

EXAMPLE 1442-[(Ethylmethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To a suspension of 5 g (0.019 mole) of2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 40 ml of absolute ethanol was added 10 ml of methylethylamine and themixture stirred at room temperature for 14 days. An additional 7.5 ml ofmethylethylamine was added and the reaction mixture heated for 18 hrvery gently and stirred at room temperature for 12 days. The solvent wasremoved by rotary evaporation. The residue was taken up in 100 ml ofmethylene chloride, washed with 2×30 ml 1N sodium hydroxide and 30 ml ofwater, dried over sodium sulfate, filtered, concentrated by rotaryevaporation and azeotroped once with toluene. The residue was reactedwith oxalic acid in isopropyl alcohol to give 2.2 g (31.3%) of crystals,m.p. 127°-131° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₅ S: C, 52.0; H, 6.28; N, 11.37.Found: C, 51.62; H, 6.27; N, 11.22.

EXAMPLE 1452-[2-(Dimethylamino)ethyl]-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-onefumarate [1:2]

To 50 ml of freshly collected dimethylamine was added 5.0 g (0.020 mole)of2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-onehydrate [1:1]. The reaction flask was sealed tightly and left standingat room temperature for 3 days. The dimethylamine was evaporated in astream of air. The residue was taken up in methylene chloride, washedtwice with 1N sodium hydroxide and once with water, dried over sodiumsulfate, filtered and concentrated by rotary evaporation. The syrupyresidue was treated with 2 equivalents of fumaric acid in isopropylalcohol which yield 5.2 g (52%) of white crystals, m.p. 164°-165° C.

Analysis: Calculated for C₂₂ H₂₉ N₃ O₁₀ : C, 53.33; H, 5.90; N, 8.48.Found: C, 53.33; H, 5.94; N, 8.44.

EXAMPLE 1462-[2-(Dimethylamino)ethyl]-3,4-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thioneoxalate [1:1]

To 40 ml of freshly collected dimethylamine was added a solution of 4.9g (0.018 mole) of2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 15 ml of methanol. The flask was sealed and left standing at roomtemperature for 3 days. The solvent was evaporated in a stream of airand the syrupy residue taken up in methylene chloride which was washedtwice with 1N sodium hydroxide and once with water, dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. The residualsyrup was treated with oxalic acid in isopropyl alcohol to give 5.5 g ofyellow crystals, m.p. 216° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O₅ S: C, 52.02; H, 56.28; N, 11.37.Found: C, 51.96; H, 6.37; N, 11.30.

EXAMPLE 1472-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-onefumarate [2:3]

To 60 ml of freshly collected dimethylamine was added 5.0 g (0.018 mole)of2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-one.The reaction flask was sealed tightly and allowed to stand 72 hr at roomtemperature. The solvent was removed by rotary evaporation and theresidue taken up in 200 ml of methylene chloride washed with 3×50 ml of1N sodium hydroxide and 100 ml of water, dried over sodium sulfate,filtered and concentrated by rotary evaporation. The residue was treatedwith fumaric acid in isopropyl alcohol to give 6.4 g (76%) of yellowcrystals, m.p. 167°-169° C.

Analysis: Calculated for C₂₀ H₂₅ N₃ O₁₀ : C, 51.39; H, 5.39; N, 8.99.Found: C, 51.47; H, 5.43; N, 8.94.

EXAMPLE 1482-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione

To 50 ml of freshly collected dimethylamine was added 4.25 g (0.014mole) of2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione.The reaction flask was sealed tightly and allowed to stand at roomtemperature for 6 days. The dimethylamine was evaporated at roomtemperature. The solid residue was taken up in methylene chloride,washed twice with 1N hydroxide and once with water, dried over sodiumsulfate, filtered and concentrated by rotary evaporation. Approximately0.8 g of the crude solid residue was triturated with isopropyl/ether togive the crystalline free base, m.p. 104°-109° C.

Analysis: Calculated for C₁₄ H₁₉ N₃ O₃ S: C, 54.35; H, 6.19; N, 13.58.Found: C, 54.20; H, 6.21; N, 13.54.

EXAMPLE 1492-[2-(Dimethylamino)ethyl]-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thionefumarate [4:3]

A sample of crude solid residue obtained in Example 148 was treated withfumaric acid in isopropyl alcohol to give the title fumarate salt. Onerecrystallization from methanol gave 2.8 g of yellow crystals, m.p.192°-194° C.

Analysis: Calculated for C₁₇ H₂₂ N₃ O₆ S: C, 51.50; H, 5.59; N, 10.60.Found: C, 51.54; H, 5.59; N, 10.47.

EXAMPLE 1502-[2-(Cyclopropylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4)-thionefumarate [1:0.5]

To a solution of 10 g (0.039 mole) of2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thionein 50 ml of dimethyl sulfoxide was added 8 g of crushed potassiumcarbonate and 5.56 g (0.098 mole) of cyclopropylamine and the mixturestirred at room temperature for 72 hr. Another 2.6 g (0.035 mole) ofcyclopropylamine was added and stirring at room temperature continuedfor 3 hr. The reaction mixture was poured into 200 ml of water andextracted with 2×100 ml of benzene. The combined organic extracts werewashed with 2×100 ml of water, dried over sodium sulfate, filtered andconcentrated by rotary evaporation. The residue was taken up in 250 mlof 1N hydrochloric acid and washed with 3×100 ml of methylene chloride.The aqueous layer was made just basic with concentrated aqueous sodiumhydroxide and extracted with 3×100 ml of methylene chloride. Thecombined organic extracts were dried over sodium sulfate, filtered, andconcentrated by rotary evaporation. The residue was further purified bypreparative HPLS using 1% triethylamine in methylene chloride. Likefractions were combined and concentrated to give ˜5 g of oil which wastreated with fumaric acid in isopropyl alcohol to give 2.8 g (21%) ofyellow crystals, m.p. 152°-154° C.

Analysis: Calculated for C₁₆ H₂₁ N₃ O₃ S: C, 57.29; H, 6.31; N, 12.53.Found: C, 57.27; H, 6.38; N, 12.42.

EXAMPLE 1512-[2-(Dimethylamino)ethyl]-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-oneoxalate[1:1]

To 60 ml of freshly collected dimethylamine was added 5.0 g (0.0195mole) of2-(2-chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-one.The reaction flask was sealed tightly and allowed to stand at roomtemperature for 72 hr. After cooling, the flask was opened and theexcess dimethylamine allowed to evaporate at room temperature. Theresidue was taken up in methylene chloride and washed twice with 1Nsodium hydroxide and once with water. The organic layer was dried oversodium sulfate, filtered, and concentrated by rotary evaporation. Theresidue was treated with oxalic acid in isopropyl alcohol to give 5.35 g(77%) of white crystals, m.p. 201°-203° C.

Analysis: Calculated for C₁₆ H₂₁ N₂ O₆ F₁ : C, 53.93; H, 5.94; N, 7.86.Found: C, 53.93; H, 5.98; N, 7.89.

EXAMPLE 1522-[2-(Dimethylamino)ethyl]-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepine-5(4H)-thioneoxalate hydrate [1:1:0.5]

To 60 ml of freshly collected dimethylamine was added 5.0 g (0.018 mole)of2-(2-chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepine-5(4H)-thione.The reaction flask was sealed tightly and allowed to stand at roomtemperature for 72 hr. After cooling, the flask was opened and theexcess dimethylamine allowed to evaporate at room temperature. Theresidue was taken up in methylene chloride, washed twice with 1N sodiumhydroxide and once with water, dried over sodium sulfate, filtered andconcentrated by rotary evaporation. The residue was treated with oxalicacid in isopropyl alcohol to give 6 g (87%) of pale yellow crystals,m.p. 180°-182° C.

Analysis: Calculated for C₁₆ H₂₂ N₂ O₅.5 S₁ F₁ : C, 50.38; H, 5.81 N,7.30. Found: C, 50.10; H, 5.65; N, 7.28.

    TABLE 2      ##STR51##                Ex. No. A(Y).sub.0-2 B R R.sup.4 E Z     ##STR52##      Salt Optical Isomer (b)       1 benz O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac. 2     benz O CH.sub.3 H O H(CH.sub.3).sub.2 (CH.sub.2).sub.2 --  3 benz O     CH.sub.3 H O      ##STR53##      (CH.sub.2).sub.2 fumarate Rac.  4 benz O CH.sub.2      φ H O     ##STR54##      (CH.sub.2).sub.2 -- Rac.  5 benz O CH.sub.2 φ H O NHCH.sub.3     (CH.sub.2).sub.2 fumarate Rac. 6 benz S CH.sub.3 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 HCl Rac. 7 benz O CH.sub.2 φ H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 H.sub.2 O Rac.      8 benz S CH.sub.3 H O     ##STR55##      (CH.sub.2).sub.2 HCl Rac.      9 naphth[2,3-f] O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     oxalate Rac. 10 pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2)     .sub.2 1.5 fumarate Rac. 11 pyrido[3,2-f] S CH.sub.3 H O N(CH.sub.3).sub.     2 (CH.sub.2).sub.2 fumarate, Rac.         0.5 ethanol 12 pyrido[3,2-f] S C     H.sub.3 H  N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.  13 benz S     CH.sub.2      φ H O     ##STR56##      (CH.sub.2).sub.2 -- Rac.      14 benz O CH.sub.3 H O NHCH.sub.3 (CH.sub.2).sub.2 fumarate Rac. 15     benz O CH.sub.3 H O NHCH.sub.3 (CH.sub.2).sub.2 -- Rac.  16 benz S     CH.sub.3 H O      ##STR57##      (CH.sub.2).sub.2 -- Rac.      17 benz S CH.sub.3 H O     ##STR58##      (CH.sub.2).sub.2 -- Rac.  18 8-Clbenz S CH.sub.3 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 HCl Rac. 19 8-Clbenz O CH.sub. 3 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 oxalate Rac. 20 7-Brbenz O CH.sub.3 H O N(CH.sub.3).sub.     2 (CH.sub.2).sub.2 oxalate Rac. 21 naph[2,1-f] O CH.sub.3 H O N(CH.sub.3)     .sub.2 (CH.sub.2).sub.2 oxalate Rac. 22 (a) pyrido[4,3-f] O CH.sub.3 H O N     (CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.   (b) pyrido[3,4-f] O     CH.sub.3 H O N(CH.sub.3).sub.2  fumarate Rac.   (c) pyrido[2,3-f] O     CH.sub.3 H O N(CH.sub.3).sub.2  fumarate Rac. 23 pyrido[4,3-f] S     CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 1.5 HCl Rac. 24 pyrido[3,     2-f] S CH.sub.3 H O N(C.sub.2 H.sub.6).sub.2 (CH.sub.2).sub.2 -- 25     naphth[2,3-f] S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate,     Rac.         1/2 H.sub.2      O 26 7,9 diiodobenz O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     -- Rac. 27 7-Clbenz O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     oxalate Rac. 28 pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2 CH.sub.2     -- Rac. 29 pyrido[3,2-f] S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.     2 methiodide Rac 30 7-Clbenz S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).     sub.2 oxzalate.1/2 Rac. 31 naphth[2,1-f] S CH.sub.3 H O N(CH.sub.3).sub.2      (CH.sub.2).sub.2 HCl H.sub.2 O Rac. 32 (a) pyrido[3,4-f] S CH.sub.3 H O N     (CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate H.sub.2 O Rac.      (b) pyrido[2,3-f] S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     fumarate H.sub.2      O Rac. 33 7-OCH.sub.3benz O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).su     b.2 oxalate.H.sub.2 O Rac.         1/2 H.sub.2 O  34 7-Brbenz S CH.sub.3     H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate.H.sub.2 O Rac. 35 (a)     benz O C.sub.6 H.sub.11 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate     Rac.   (b) benz O C.sub.2 H.sub.5 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     oxalate Rac.   (c) benz O CH(CH.sub.3).sub.2 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 oxalate Rac.   (d) benz O 4-ClC.sub.6 H.sub.4 CH.sub.2     H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.   (e) benz O     4-CH.sub.3C.sub.6 H.sub.4      CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.   (f) benz     O 3,5-(OCH.sub. 3).sub.2C.sub.6 H.sub.5 CH.sub.2 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 oxalate Rac.   (g) benz O 3-CF.sub.3C.sub.6 H.sub.4     CH.sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.   (h) benz     O 4-NO.sub.2C.sub.6 H.sub.4      CH.sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac. 36 (a)     pyrido[3,2-b] O C.sub.6 H.sub.11 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     fumarate Rac.   (b) pyrido[3,2-f] O C.sub.2      H.sub.5 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.   (c)     pyrido[3,2-f] O CH(CH.sub.3).sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2      fumarate Rac.   (d) pyrido[3,2-f] O 4-ClC.sub.6 H.sub.4 CH.sub.3 H O     N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.   (e) pyrido[3,2-f] O     4-CH.sub.3C.sub.6 H.sub.4      CH.sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.   (f)     pyrido[3,2-f] O 4-OCH.sub.3C.sub.6 H.sub.4      CH.sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.   (g)     pyrido[3,2-f] O 3-CF.sub.3C.sub.6 H.sub.4 CH.sub.2 H O N(CH.sub.3).sub.2 (     CH.sub.2).sub.2 fumarate Rac.   (h) pyrido[3,2-f] O 4-NO.sub.2C.sub.6     H.sub.4 CH.sub.2 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac. 37     (a) benz O CH.sub.3 H O 1-pyrrolidinyl (CH.sub.2).sub.2 fumarate Rac.     (b) benz O CH.sub.3 H O 1-piperidinyl (CH.sub.2).sub.2 fumarate Rac.     (c) benz O CH.sub.3 H O 1-piperazinyl (CH.sub.2).sub.2 fumarate Rac.     (d) benz O CH.sub.3 H O 4-CH.sub.3piperizinyl (CH.sub.2).sub.2 fumarate     Rac. 38 pyrido[3,2-f] O CH.sub.3 H S N(CH.sub.3).sub.2 (CH.sub.2).sub.2     2.HCl Rac. 39 pyrido[3,2-f] S CH.sub.3 H S N(CH.sub.3).sub.2 (CH.sub.2).s     ub.2 oxalate Rac. 40 pyrido[3,4-f] O CH.sub.3 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 1/2 H.sub.2 O 2 oxalate Rac. 41 pyrido[3,4-f] S     CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 oxalate Rac. 42     pyrido[3,2-f] O CH.sub.3 H O NH.sub.2 (CH.sub.2).sub.3 1/2 H.sub.2 O     oxalate Rac.      43 pyrido[3,2-f] O CH.sub.3 H O     ##STR59##      (CH.sub.2).sub.2 maleate Rac.      44 pyrido[3,2-f] O CH.sub.3 H O 1-pyrrolidinyl (CH.sub.2).sub.2 2     fumarate Rac. 45 pyrido[3,2-f] O CH.sub.3 H O N(n-butyl).sub.2 (CH.sub.2)     .sub.2 maleate Rac. 46 pyrido[3,2-f] O CH.sub.3 H O N(C.sub.2      H.sub.6).sub.2 (CH.sub.2).sub.2 oxalate Rac. 47 pyrido[3,2-f] O     CH.sub.3 H O 1-piperidinyl (CH.sub.2).sub.2 oxalate Rac. 48 pyrido[3,2-f]      O CH.sub.2 H O N(CH.sub.3)(benzyl) (CH.sub.2).sub.2 maleate Rac. 49     pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3)C.sub.6 H.sub.5 (CH.sub.2).sub.2     -- Rac.      50 pyrido[3,2-f] O CH.sub.3 H O     ##STR60##      (CH.sub.2).sub.2 fumarate Rac.  51 pyrido[3,2-f] O CH.sub.3 H O      ##STR61##      (CH.sub.2).sub.2 -- Rac.      52 pyrido[3,2-f] O CH.sub.3 H O     ##STR62##      (CH.sub.2).sub.2 -- Rac.      53 pyrido[3,2-f] O CH.sub.3 H O     ##STR63##      (CH.sub.2).sub.2 -- Rac.  54 pyrido[3,2-f] O C.sub.2 H.sub.6 H O     N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac. 55 pyrido[3,2-f] O     C.sub.2 H.sub.6 H O 1-pyrrolidinyl (CH.sub.2).sub.2 oxalate Rac.  56     pyrido[3,2-f] S CH.sub.3 H O      ##STR64##      (CH.sub.2).sub.2 -- Rac.      57 pyrido[3,2-f] S CH.sub.3 H O N(n-butyl).sub.2 (CH.sub.2).sub.2     oxalate Rac. 58 pyrido[3,2-f] S CH.sub.3 H O N(C.sub.2 H.sub.6).sub.2     (CH.sub.2).sub.2 oxalate Rac. 59 pyrido[3,2-f] S CH.sub.3 H O 1-pyrrolidi     nyl (CH.sub.2).sub.2 oxalate Rac.  60 pryido[3,2-f] S CH.sub.3 H O      ##STR65##      (CH.sub.2).sub. 2 1.5 oxalate Rac.  61 pyrido[3,2-f] S C.sub.2 H.sub.5     H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 -- Rac. 62 pyrido[3,2-f] S     CH.sub.3 H O N(CH.sub.3)(benzyl) (CH.sub.2).sub.2 oxalate Rac. 63     pyrido[3,2-f] S CH.sub.3 H O NHCH.sub.3 (CH.sub.2).sub.2 1.5 oxalate     Rac. 64 7-Clpyrido[3,2-f] O CH.sub.3 H O 1-pyrrolidinyl (CH.sub.2).sub.2     2.5 fumarate Rac. 65 7-Clpyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2     (CH.sub.2).sub.2 oxalate Rac. 66 pyrido[3,2-f] O C.sub.6 H.sub.11 H O     N(CH.sub.3).sub.2 CH.sub.2 oxalate Rac. 67 pyrido[3,2-f] O CH.sub.2     C.sub.6 H.sub.5 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 1.5 oxalate, 1/2     H.sub.2      O Rac. 68 (a) pyrido[3,2-f] O H H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     -- Rac. 68 (b) pyrido[3,2-f] O H H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     fumarate Rac. 69 pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2     ).sub.3 1.5 fumarate, Rac.         0.5 H.sub.2 O 70 pyrido[3,2-f] S     CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 oxalate Rac. 71     7-Clpyrido[3,2-f] S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 1/2     H.sub.2 O, Rac.         1/2 (CH.sub.3).sub.2 HOH 72 prydio[3,2-f] O     CH.sub.3 H O NHCH.sub.3 (CH.sub.2).sub.2 oxalate Rac. 73 pyrido[3,2-f] O C     H.sub.3 H O NH.sub.2 (CH.sub.2).sub.2 fumarate Rac. 74 pyrido[3,2-f] S     CH.sub.3 H O NH.sub.2 (CH.sub.2).sub.2 0.5 fumarate Rac.      75 pyrido[3,2-f] O CH.sub.3 H O      ##STR66##      (CH.sub.2).sub.2 2.0 fumarate Rac.  76 pyrido[3,2-f] S CH.sub.3 H O     N(CH.sub.2 C.sub.6 H.sub.5).sub.2 (CH.sub.2).sub.2 fumarate Rac. 77     pyrido[3,2-f] O CH.sub.3 H O 4-methylpiperazin-1-yl (CH.sub.2).sub.2 2.0     fumarate, Rac.         hydrate 78 pyrido[3,2-f] S CH.sub.3 H O 4-methylpi     perazin-1-yl (CH.sub.2).sub.2 2.0 fumarate, Rac.         1/2 H.sub.2 O     79 pyrido[3,2-f] O CH.sub.3 H O (a) (CH.sub.2).sub.2 2.0 fumarate, Rac.            1/2 H.sub.2 O      80 pyrido[3,2-f] O CH.sub.3 H O     ##STR67##      (CH.sub.2).sub.2 oxalate Rac.      81 pyrido[3,2-f] S CH.sub.3 H O N(CH.sub.3)(C.sub.6 H.sub.5) (CH.sub.     2).sub.2 -- Rac. 82 pyrido[3,2-f] S CH.sub.3 H O NH.sub.2 (CH.sub.2).sub.     2 fumarate Rac. 83 pyrido[3,2-f] S H H O N(CH.sub.3).sub.2 (CH.sub.2).sub     .2 2 HCl, H.sub.2      O Rac. 84 pyrido[3,2-f] S CH.sub.3 H O (a) (CH.sub.2).sub.2 oxalate,     H.sub.2 O Rac.      85 pyrido[3,2-f] S CH.sub.3 H O     ##STR68##      (CH.sub.2).sub.2 -- Rac.      86 pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2      ##STR69##      oxalate Rac.      87 pyrido[3,2-f] S CH.sub.3 H O     ##STR70##      (CH.sub.2).sub.2 1.5 oxalate Rac.  88 pyrido[3,2-f] O CH.sub.3 CH.sub.3     O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 HCl Rac. 89 pyrido[3,2-f] S     CH.sub.3 CH.sub.3 O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  90      ##STR71##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  91     pyrido[3,2-f] S CH.sub.3 H O N(CH.sub.3).sub.2      ##STR72##      oxalate Rac.  92 pyrido[3,2-f] O CH.sub.3 H O N(CH.sub.3).sub.2      ##STR73##      HCl Rac.      93 pyrido[3,2-f] S CH.sub.3 H O     ##STR74##      (CH.sub.2).sub.2      ##STR75##      Rac.      94     ##STR76##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate Rac.  95      ##STR77##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate, 0.5 H.sub.2     O Rac.      96     ##STR78##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 fumarate,isopropylalco     hol, H.sub.2 O Rac.  97 benz O C.sub.2      H.sub.5 H     ##STR79##      ##STR80##      (CH.sub.2).sub.2 fumarate,isopropylalcohol Rac.  98 benz O C.sub.2     H.sub.5 H      ##STR81##      ##STR82##      (CH.sub.2).sub.2 -- Rac.      99 benz O CH(CH.sub.3).sub.2 H     ##STR83##      N(CH.sub.3).sub.2 CH.sub.2 -- Rac.  100 benz O C.sub.2 H.sub.5 H      ##STR84##      N(CH.sub.3).sub.2 (CH.sub.2).sub.2 -- Rac.  101 pyrido[3,2-f] S     CH.sub.3 H O      ##STR85##      (CH.sub.2).sub.2      ##STR86##      Rac.      102 6-Clpyrido[4,3-f] O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     0.5 fumarate Rac. 103 6-[N(CH.sub.3).sub.2 ]pyrido[4,3-f] O CH.sub.3 H O N     (CH.sub.3).sub.2 (CH.sub.2).sub.2 1.5 fumarate Rac.  104 pyrido[3,2-f] O C     H.sub.3 H O      ##STR87##      (CH.sub.2 ).sub.2 2.0 fumarate Rac.  105 pyrido[3,2-f] S CH.sub.3 H O      ##STR88##      (CH.sub.2).sub.2 fumarate Rac.  106 pyrido[3,2-f] O CH.sub.3 H O      ##STR89##      (CH.sub.2).sub.2 oxalate, 0.5 H.sub.2 O Rac.  107 pyrido[3,2-f] O     CH.sub.3 H O N(CH.sub.3).sub.2 CH.sub.2 fumarate Rac. 108 pyrido[3,2-f]     S CH.sub.3 H O N(CH.sub.3).sub.2 CH.sub.2 0.5 fumarate Rac. 109 pyrido[3,     2-f] O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 -- Rac.  110      ##STR90##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  111      ##STR91##      S  CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  112      ##STR92##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  113      ##STR93##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  114      ##STR94##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  115      ##STR95##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2  HCl Rac.  116      ##STR96##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  117      ##STR97##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  118      ##STR98##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  119      ##STR99##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  120      ##STR100##      O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac.  121      ##STR101##      S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 HCl Rac.  122     pyrido[3,2-f] O CH.sub.3 H O      ##STR102##      (CH.sub.2).sub.2 oxalate, 0.5 H.sub.2 O Rac.  123 pyrido[3,2-f] S     CH.sub.3 H O      ##STR103##      (CH.sub.2).sub.2 fumarate Rac.      124 7-Clbenz- S CH.sub.3 H O     ##STR104##      (CH.sub.2).sub.2 oxalate 0.5 H.sub.2 O Rac.  125 pyrido[3,2-f]- S     CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 HCl S(+) 126 pyrido[3,2     -f]- S CH.sub.3 H O  N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 HCl R(-)  127     pyrido[3,2-f] S CH.sub.3 H O      ##STR105##      (CH.sub.2).sub.2      ##STR106##      Rac.  128 7-Clpyrido[3,2-f]- O CH.sub.3 H O N(CH.sub.2 H.sub.5).sub.2     (CH.sub.2).sub.2 oxalate Rac.  129 7-Clpyrido[3,2-f]- O CH.sub.3 H O      ##STR107##      (CH.sub.2).sub.2 oxalate Rac.  130 7-Clpyrido[3,2-f]- O CH.sub.3 H O     N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5 (CH.sub.2).sub.2 oxalate Rac. 131     7-Clpyrido[3,2-f] O CH.sub.3 H O NHCH.sub.3 (CH.sub.2).sub.2 oxalate     Rac. 132 7-Brpyrido[3,2-f]- O CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).s     ub.2 oxalate Rac.      133 7-Brpyrido[3,2-f] O CH.sub.3 H O     ##STR108##      (CH.sub.2).sub.2 oxalate Rac.  134 7-Brpyrido[3,2-f]- O CH.sub.3 H O     N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5 (CH.sub.2).sub.2 oxalate Rac.  135     7-Brpyrido[3,2-f]- S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2     oxalate Rac.      136 7-Brpyrido[3,2-f]- S CH.sub.3 H O     ##STR109##      (CH.sub.2).sub.2 oxalate Rac.  137 7-Clpyrido[3,2-f]- S CH.sub.3 H O      ##STR110##      (CH.sub.2).sub.2 fumarate Rac.  138 7-Clpyrido[3,2-f]- S CH.sub.3 H O     NHCH.sub.3 (CH.sub.2).sub.2 oxalate Rac.  139 7-Clpyrido[3,2-f]- S     CH.sub.3 H O      ##STR111##      (CH.sub.2).sub.2 oxalate Rac.  140 7-Brpyrido[3,2-f]- S CH.sub.3 H O     N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5 (CH.sub.2).sub.2 oxalate Rac. 141     7-Clpyrido[3,2-f]- S CH.sub.3 H O N(C.sub.2      H.sub.5).sub.2 (CH.sub.2).sub.2 fumarate Rac. 142 7-Clpyrido[3,2-f]- S     CH.sub.3 H O N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5 (CH.sub.2).sub.2     oxalate Rac. 143 pyrido[3,2-f]- O CH.sub.3 H O N(CH.sub.3)C.sub.2     H.sub.5 (CH.sub.2).sub.2 oxalate Rac. 144 pyrido[3,2-f]- S CH.sub.3 H O     N(CH.sub.3)C.sub.2      H.sub.5 (CH.sub.2).sub.2 oxalate Rac. 145 8-CH.sub.3pyrido[3,2-f]- O     CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 2 fumarate Rac. 146     8-CH.sub.3pyrido[3,2-f]- S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.     2 oxalate Rac. 147 7-NO.sub.2pyrido[3,2-f]- O CH.sub.3 H O N(CH.sub.3).su     b.2 (CH.sub.2).sub.2 1.5 fumarate Rac. 148 7-NO.sub.2pyrido[3,2-f]- S     CH.sub.3 H O N(CH.sub.3).sub.2  (CH.sub.2).sub.2 -- Rac. 149 7-NO.sub.2py     rido[3,2-f]- S CH.sub.3 H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 3/4     fumarate Rac.      150 pyrido[3,2-f]- S CH.sub.3 H O     ##STR112##      (CH.sub.2).sub.2 0.5 fumarate Rac.  151 7-Fbenz- O CH.sub.3 H O     N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate Rac. 152 7-Fbenz- S CH.sub.3     H O N(CH.sub.3).sub.2 (CH.sub.2).sub.2 oxalate 0.5 H.sub.2     Footnote:     ##STR113##     (b) Rac = racemic mixture

Additional Pharmacology

Experiments were conducted to determine whether sedation was present asa result of administration of the compounds of the invention asantihistaminics and the results on compounds tested suggests they arenon-sedative antihistaminics. The comparative antihistaminic agent usedwas diphenhydramine which does cause sedation. See Douglas, W. C.(1980), "Histamine and 5-hydroxytryptamine (serotonin) and theirantagonists" in The Pharmacological Basis of Therapeutics (ed: A. G.Gilman, L. S. Goodman, A. Gilman, 6th edition, Macmillan, New York, pp609-641. In the present tests, sedation is defined as a change in theelectroencephalograms (EEGs) from the normal pattern of low voltage,fast (β) cerebral cortical waves (12-25 Hz, >50 mV amplitude) tosynchronized high voltage, slow (α, Δ) cerebral cortical waves (1-3, 4-7Hz, >50 mV amplitude) with frequent periods of sleep spindlespredominating.

Experimental Method for Sedative Activity

Ten cats of both sexes were anesthetized with halothane and cannulaeplaced in the trachea, the left cephalic vein, and the right femoralartery for artificial ventilation, drug administration, and bloodpressure recording, respectively. The head was fixed in a Kopfstereotaxic unit and the calvarium was widely exposed. Stainless steelscrew electrodes (1/4') were placed through the calvarium so that thetips rested on the dura over the frontal, parietal, and occipital areas,bilaterally. An electrode of the same type was placed in the rightfrontal sinus and served as the reference electrode for monopolar EEGrecordings. After completion of the surgery, the animal was givengallamine triethiodide (20 mg, IV; supplemented as necessary) and thehalothane withdrawn. Artificial respiration was instituted (10 ml roomair/kg/3 sec).

EEGs were made on a Grass, Model 5, electroencephalograph along with(lead II) EKG. Typically, EEGs were recorded for 2-3 min every 10 min.Arterial blood pressure was continuously monitored on a Grass, Model 79,polygraph.

In most experiments, histamine (0.5 μg/kg, IV) was given to produce atransient (<30 sec) hypotensive effect. It was normally given 10, 20 and30 min prior to the first dose of the test drug and then 5, 10 and 20min after each dose of the test drug. In this way an indication of theantihistaminic activity of test drug could be quantified.

Concomitant with the antihistaminic quantification was the effect oftest drug on EEG. Test drug was usually given in increasing doses of0.1, 0.3, 0.5, 1, 3, 5, 10 and 20 mg/kg, IV.

Experimental Results on Sedative Potential

Illustratively of the compounds tested (Examples 12, 65 and 71) thecompound of Example 12 produced a 50% reduction of the histamine-induceddepressor effect on blood pressure at 0.3 mg/kg, IV and a 100%suppression at 1-3 mg/kg, IV. There were no signs of sedation in theseanimals at any dose up to 20 mg/kg, IV.

On the other hand, the comparative drug, diphenhydramine, known toproduce sedation (tested here in 6 cats) produced a 50% suppression ofthe histamine-induced depressor effect on blood pressure at 0.5 mg/kg,IV and a 100% suppression at 3-5 mg/kg, IV. Signs of sedation withdiphenhydramine occurred in the EEG tracings as low as 0.5 mg/kg, IVwith marked slowing, synchronized waves, and sleep spindles at 1-3mg/kg, IV. In summary, diphenhydramine produced an antihistaminic effectin doses which also produced a sedative effect. This is similar to whatis seen in man with diphenhydramine.

In contrast to the effects of diphenhydramine, compounds such as that ofExample 12 do not produce sedation at any dose up to 20 mg/kg, eventhough the antihistaminic effects occurred at much lower doses. Thesedata, therefore, suggest the nonsedative nature of compounds of theinvention.

Pharmaceutical Compositions

The invention further provides pharmaceutical compositions foradministration to a living animal body comprising, as activeingredients, at least one of the compounds of Formula I according to theinvention in association with a pharmaceutical carrier or excipient. Thecompounds are thus presented in a therapeutic composition suitable fororal, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal,intravenous, or intranasal administration. Thus, for example,compositions for oral administration can take the form of elixirs,capsules, tablets or coated tablets containing carriers convenientlyused in the pharmaceutical art. Suitable tableting excipients includelactose, potato and maize starches, talc, gelatin and stearic andsilicic acids, magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient can be comprisedof a sterile parenterally acceptable liquid; e.g., water or arachis oilcontained in ampoules.

In compositions for rectal administration, the carrier can be comprisedof a suppository base; e.g., cocoa butter or a glyceride.

Application to the nose, throat or bronchial region can be in the formof gargle or an aerosol spray containing small particles of the agent ofFormula I in a spray or dry powder form.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage forms according to the invention, It isonly necessary that the active ingredient constitute an effectiveamount; i.e., such that a suitable effective dosage will be consistentwith the dosage from employed. The exact individual dosages, as well asdaily dosages, will of course be determined according to standardmedical principles under the direction of a physician or veterinarian.Generally, the pharmacology tests on guinea pigs in comparison tocertain other antihistaminic drugs and limited testing in humanssuggests an effective dose for an adult will be in the range of 1 to 50mg for the more active compounds.

Based on the animal data and limited human testing, unit dosagescontaining an amount of compound equivalent to about 0.01 to about 1.0mg of active drug per kilogram of body weight are contemplated. Dailydosages of about 0.04 to 4.0 mg/kg body weight are contemplated forhumans and obviously several small unit dosage forms may be administeredat one time. However, the scope of the invention is not to be limited bythese contemplations due to uncertainty in transposing from animal datato humans and preliminary human testing.

Examples of unit dosage compositions are as follows:

    ______________________________________                                        Ingredients       Per Capsule                                                 ______________________________________                                        Capsules:                                                                     1.      Active ingredient                                                                           4           mg.                                         2.      Lactose       150         mg.                                         3.      Magnesium stearate                                                                          4           mg.                                         Tablets:                                                                      1.      Active ingredient                                                                           4           mg.                                         2.      Corn starch   20          mg.                                         3.      Kelacid       20          mg.                                         4.      Keltose       20          mg.                                         5.      Magnesium stearate                                                                          1.3         mg.                                         ______________________________________                                    

Procedure for tablets:

1. Blend 1, 2, 3, and 4 in larger amounts.

2. Add sufficient water portionwise to blend to the blend from step 1with careful stirring after each addition. Such additions of water andstirring continue until the mass is of a constituency to permit itsconversion to wet granules.

3. The wet mass is converted to granules by passing it through theoscillating granulator using 8 mesh screen.

4. The wet granules are then dried in an oven at 140° F.

5. The dry granules are lubricated with the magnesium stearate.

6. The lubricated granules are compressed on a suitable tablet press.

    ______________________________________                                                            Per ml.                                                   ______________________________________                                        1.    Active ingredients  10.0      mg.                                       2.    Isotonic buffer solution 4.0 q.s to                                                               1.0       ml.                                       ______________________________________                                    

Procedure:

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step 1.

3. The sterile solution is now aseptically filled into sterile ampuls.

4. The ampuls are sealed under aseptic condition.

Suppositories:

    ______________________________________                                        Ingredients         Per Supp.                                                 ______________________________________                                        1.     Active ingredient                                                                              10.0       mg.                                        2.     Polyethylene Glycol 1000                                                                       1350.0     mg.                                        3.     Polyethylene Glycol 4000                                                                       450.0      mg.                                        ______________________________________                                    

Procedure:

1. Melt 2 and 3 together and stir until uniform.

2. Dissolve No. 1 in the molten mass from step 1 and stir until uniform.

3. Pour the molten mass from step 2 into suppository molds and chill.

4. Remove the suppositories from molds and wrap.

Therapeutic compositions for combatting histamine in unit dosage form,comprising a pharmaceutical carrier and an effective amount of acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof are therefore an embodiment of this invention.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, methods, processes andpharmaceutical compositions of the present invention without departingfrom the spirit and scope thereof, and it is therefore to be understoodthat the invention is to be limited only by the scope of the appendedclaims.

What is claimed is:
 1. A compound selected from the group having theformula: ##STR114## wherein A represents a pyridine in any of its fourpositins optionally substituted by one or two Y radicals selected fromthe group consisting of halo, loweralkyl containing up to eight carbonatoms, loweralkoxy containing up to eight carbon atoms,diloweralkylamino wherein each loweralkyl group contains up to eightcarbon atoms, nitro or trifluoromethyl;R is selected from the groupconsisting of loweralkyl containing up to eight carbon atoms, cycloalkylcontaining 3-9 carbon atoms, or phenyl-loweralkyl wherein the loweralkylcontains up to eight carbon atoms and the phenyl is optionallysubstituted by one or two radicals selected from halo, loweralkylcontaining up to eight carbon atoms, lowralkoxy containing up to eightcarbon atoms, nitro or trifluoromethyl; n is 1 or 2; R⁴ and R⁵ areselected from hydrogen or loweralkyl (1-5c); Q is selected from thegroup consisting of ##STR115## wherein R3 is hydrogen or an alkali metalion and E is oxygen or sulfur.
 2. The compound of claim 1 which issodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate or thefree base thereof.
 3. The compound of claim 1 which is3-[(1-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile or its fumaratesalt.